Condensed heterocyclic compounds, their production and use

ABSTRACT

Novel compound represented by the formula:  &lt;IMAGE&gt;  wherein A&#39;&#39;, B, C, D, E, G, Ar, X, Y, and Z are defined herein or a salt thereof. The compounds have excellent activity of inhibiting ACAT, lowering Cholesterol in blood and inhibiting tachykinin receptor, or a salt thereof, their production and use.

This application is a division of application Ser. No. 08/114,841, filedSep. 2, 1993 now U.S. Pat. No. 5,482,967.

The present invention relates to a new condensed heterocyclic compoundwhich excellently inhibits the enzyme acyl-CoA:cholesterol acyltransferase (ACAT) and has a high tachykinin receptor antagonizingactivity.

With respect to the compound wherein a phenyl group and a group of theformula: ##STR2## (m is 0 or 1) adjacently substitute on a heterocyclicring resulting from condensation of a 6-membered heterocyclic ring and abenzene ring, known compounds include (1) the compound represented bythe formula: ##STR3## wherein Ar represents an aryl group, described inthe Indian Journal of Chemistry, Section B, 26B, Vol. 8, pp. 744-747(1987), (2) the compound represented by the formula: ##STR4## wherein R¹represents an alkyl, aryl or cyclohexyl group, described in the ChemicalAbstract, Vol. 107, 175835f, (3) the compound represented by theformula: ##STR5## wherein R represents benzyl or 4-methylphenyl and R¹represents a methyl, ethyl, naphthyl, benzyl or phenyl group, describedin the Chemical Abstract, Vol. 114, 42492q, (4) the compound representedby the formula: ##STR6## wherein Ph represents a phenyl group; R¹represents an hydrogen atom or bromine; R² represents an alkyl, aryl orbenzyl group, described in the Chemical Abstract, Vol. 107, 115463y, and(5) the compound represented by the formula: ##STR7## wherein R²represents a phenyl, o-, m- or p-methylphenyl or 4-chlorophenyl group;R³ represents a phenyl, benzyl, allyl, ethyl, butyl, isobutyl or t-butylgroup, described in the Chemical Abstract, Vol. 93, 220536q.

Also, publication (1) describes that pyrrolo 2,3-b!quinoline seriescompounds exhibit anti-inflammatory, antibacterial, hypotensive,antipyretic and antispasmodic actions and possess interferon-inducingactivity. As for publications (2) to (5), no action is described butmethods of synthesizing the respective compounds are described.

However, there have been no reports concerning whether theseconventional compounds exhibit ACAT-inhibitory action, arteriosclerosistherapeutic effect, blood cholesterol lowering action and tachykininreceptor antagonizing action.

As compounds having substance P receptor antagonizing activity, thefollowing (6) to (13) are known. (6) In EP-A-333,174, a compound of theformula:

    R.sup.1 --A--D-Trp(R.sup.2)-Phe-R.sup.3

wherein R¹ is hydrogen or an amino-protecting group; R² is hydrogen, anamino-protecting group, a carbamoyl(lower)alkyl group, acarboxy(lower)alkyl group; R³ is an ar(lower)alkyl group, a group of theformula: ##STR8## wherein R⁴ and R⁵ are each hydrogen, aryl or loweralkyl which may have suitable substituent(s), or R⁴ and R⁵ are linkedtogether to form benzene-condensed lower alkylene or a group of theformula:

    --OR.sup.6

wherein R⁶ is hydrogen, aryl or lower alkyl which may have suitablesubstituent(s); A is a single bond or one or two amino acids residue,provided when A is one amino acid residue of --D-Trp--, then R⁴ is nothydrogen; and a salt thereof, (7) in EP-A-436,334 among others, acompound of the formula: ##STR9## (8) in EP-A-429,366 among others, acompound of the formula: ##STR10## (9) in Journal of MedicinalChemistry, 34, p1751, 1991 among others, a compound of the formula:##STR11## (10) in WO91/09844, a compound of the formula: ##STR12## (11)in EP-A-522,808, a compound of the formula: ##STR13## (12) inWO93/01169, a compound of the formula: ##STR14## (13) in EP-A-532,456, acompound of the formula: ##STR15## And, the following (14), (15) and(16) are known for isoquinoline derivatives. (14) in Farmaco, EdizioneScientifica, 36, 400-411 (1981), a compound of the formula: ##STR16##(15) in Chemical Abstract, 107, 39507(1987), a compound of the formula:##STR17## (16) Archiv der Pharmazie, 324, 809-814 (1991), a compound ofthe formula: ##STR18## wherein R¹ represents hydrogen, methyl, n-butyl,cyclohexyl, benzyl, isopropyl; R² represents hydrogen, 10-methyl,11-methyl, 10-chloro, 11-chloro, 12-fluoro, 12-bromo; R³ representshydrogen, 6-chloro, 7-chloro, 6-bromo.

With respect to a bioactivity of a compounds described in (14) to (16),there is disclosure about local anesthesia action in (14), antibacterialaction in (15) and anticonvulsion action in (16). However, there is nodisclosure ever suggesting that these compounds have ACAT-inhibitoryaction, blood cholesterol lowering action and tachykinin receptorantagonizing action.

Against this background, there has been demand for the development of acompound which exhibits excellent ACAT-inhibitory action, whichsuppresses intestinal cholesterol absorption and arterial wallcholesterol ester accumulation in mammals, and which is useful as aprophylactic and therapeutic composition for hypercholesterolemia,atheromatous arteriosclerosis and various diseases associated therewith(e.g., ischemic heart diseases such as myocardial infarction andcerebrovascular disorders such as cerebral infarction and cerebralstroke).

And, tachykinin is a generic term denoting a group of neuropeptides. Inmammalian animals, substance P, neurokinin-A and neurokinin-B are known.It is also known that by binding their respective receptors(neurokinin-1, neurokinin-2, neurokinin-3) present in the living body,these peptides exhibit a diversity of biological activities.

Among them, substance P is a neuropeptide known for the longest time ofall and studied in the greatest detail. Substance P is known to play acritical role as a transmitter substance in both the peripheral andcentral nervous systems. This substance is also suspected to be involvedin a variety of morbid states (pain, inflammation, allergy, faciltationof micturition, mental disease, airway-diseases, etc.). Such being thecase, for use as drugs for the treatment of the above-mentioned diseasestates, the development of compounds having potent tachykinin receptorantagonizing activity, particularly high antagonistic activity againstsubstance P receptor, as well as other favorable properties such assafety and a sufficiently long duration of action after administrationhas been looked after in earnest.

This invention concerns certain heterocyclic compounds which inhibit theenzyme ACAT, pharmaceutical compositions containing these compounds, anda method of treating hypercholesterolemia and artherosclerosis and soon, and antagonize the tachykinin receptor, pharmaceutical compositionscontaining these compounds, and a method of treating pain, disturbancesof micturition and inflammation and so on.

(1) A compound of this invention is represented by the following generalformula: ##STR19## wherein ring A may be substituted; ring B representsan optionally substituted benzene ring;

either X or Y represents --NR¹ -- (R¹ represents a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedhydroxyl group or an optionally substituted amino group), --O-- or--S--, the other representing --CO--, --CS-- or --C(R²)R^(2a) -- (R² andR^(2a) independently represent a hydrogen atom or an optionallysubstituted hydrocarbon group), or either X or Y represents --N═, theother representing ═CR³ -- (R³ represents a hydrogen atom, a halogenatom, an optionally substituted hydrocarbon group, an optionallysubstituted amino group, a substituted hydroxyl group or a mercaptogroup substituted by an optionally substituted hydrocarbon group);

........ represents a single or double bond;

(i) when ........ adjacent to Z is a single bond, Z represents ##STR20##(R⁴ represents a hydrogen atom, a hydroxyl group or an optionallysubstituted hydrocarbon group) or a nitrogen atom, or (ii) when ........adjacent to Z is a double bond, Z represents a carbon atom;

D represents a C₁₋₃ alkylene group which may be substituted by an oxo orthioxo group, or D and Y, taken together, may form a 5- to 7- memberedring which may be substituted by an oxo or thioxo group;

E represents --NR⁵ -- (R⁵ represents a hydrogen atom or an optionallysubstituted hydrocarbon group), --O-- or --S(O)n-- (n is 0,1 or 2), orR⁵ and Y, taken together, may form a 5- to 7-membered ring which may besubstituted by an oxo or thioxo group;

G represents a bond or a C₁₋₃ alkylene group;

Ar represents an optionally substituted aryl group or an optionallysubstituted heterocyclic group, provided that, (1) when (i)--X--Y--represents --O--CO-- or --CO--O--, (ii) D represents --CO-- and(iii) E represents --NR⁵ --, either (a) G represents a C₁₋₃ alkylenegroup and Ar represents a substituted aryl group or a substitutedheterocyclic group, or (b) G represents a bond and R⁵ represents anoptionally substituted hydrocarbon group, and (2) when --X--Y--represents --NH--CO--, D represents --CO--, or a salt thereof, (2) acomposition for inhibiting acyl-CoA: cholesterol acyl transferase,lowering cholesterol in blood and having tachykinin receptorantagonizing activity which comprise an effective amount of a compoundof the formula: ##STR21## wherein the symbols are as defined aboveexcluding for the "provided" clause, or a pharmaceutically acceptablesalt and a physiologically acceptable carrier, (3) a process forproducing the above compound (I) or a salt thereof which comprisesreacting a compound of the formula: ##STR22## wherein L represents aleaving group; D and Y do not bind together to form a 5- to 7-memberedring; the other symbols are the same meaning as defined hereinabove orsalt thereof with a compound of the formula:

    H--E--G--Ar                                                (III)

wherein all symboles are the some meaning as defined hereinabove or asalt thereof, (4) a process for producing the above compound (I) or asalt thereof, which comprises reacting a compound of the formula:##STR23## wherein all symboles are the same meaning as definedhereinabove or salt thereof with a compound of the formula:

    L'--G--Ar                                                  (V)

wherein L' represents a leaving group; the other symboles are the samemeaning as defined hereinabove or a salt thereof.

With respect to the above formula, the ring A represents an optionallysubstituted ring. The ring A represents a moiety of the formula:##STR24##

The ring B represents an optionally substituted benzene ring.Preferably, the ring A and B each is a benzene ring which may besubstituted.

The substituent(s) that may be present on ring A and B include, amongothers, halogen atom, optionally halogenated alkyl group, optionallyhalogenated alkoxy group, optionally halogenated alkylthio group, C₁₋₇acylamino group (e.g. formylamino, acetylamino, propionylamino,butyrylamino, benzoylamino, etc.), C₁₋₃ acyloxy group (e.g. formyloxy,acetoxy, propionyloxy, etc.), hydroxyl, nitro, cyano, amino, mono- ordi-C₁₋₄ alkylamino group (e.g. methylamino, ethylamino, propylamino,dimethylamino, diethylamino, etc.), cyclic amino group (e.g., 5- to9-membered cyclic amino which may consist 1 to 3 hetero-atoms such asoxygen and sulfur in addition to nitrogen as ring-constituent members,such as pyrrolidino, piperidino, morpholino, etc.), C₁₋₄alkyl-carbonylamino group (e.g. acetylamino, propionylamino,butyrylamino, etc.), C₁₋₄ alkylsulfonylamino group (e.g.methylsulfonylamino, ethylsulfonylamino, etc.), C₁₋₄ alkoxy-carbonylgroup (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.),carboxyl, C₁₋₆ alkyl-carbonyl group (e.g. methylcarbonyl, ethylcarbonyl,propylcarbonyl, etc.), carbamoyl, ethylcarbamoyl, etc.), mono- ordi-C₁₋₄ alkylcarbamoyl group(e.g. methylcarbamoyl, ethylcarbamoyl,etc.:) and C₁₋₆ alkylsulfonyl group (e.g. methylsulfonyl, ethylsulfonyl,propylsulfonyl, etc.).

As the halogen atom, among the above-mentioned substituents, fluoro,chloro, bromo and iodo may be used and chloro or fluoro is preferred.

Examples of the optionally halogenated alkyl group includestraight-chain or branched alkyl group having 1 to 6 carbon atoms andsuch alkyl groups substituted by 1 to 5 halogen atoms (e.g., fluorine,chlorine, bromine and iodine, preferably chlorine, bromine etc.).Specifically, commonly used alkyl group include methyl, chloromethyl,difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl,isopropyl, 2-trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl,isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,5,5,5-trifluoropentyl, 4-trifluoromethyl-butyl, hexyl,6,6,6-trifluorohexyl and 5-trifluoromethylpentyl. Preferably used arestraight-chain or branched alkyl groups having 1 to 4 carbon atoms suchas methyl, chloromethyl, difluoromethyl, trichloromethyl,trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, propyl,3,3,3-trifluoropropyl, isopropyl, 2-trifluoromethylethyl, butyl,4,4,4-trifluorobutyl, isobutyl, sec-butyl and tert-butyl, or such alkylgroups substituted for by 1 to 3 of the above-mentioned halogen atoms.

Examples of the alkoxy group which may be substituted by halogen and thealkylthio group which may be substituted by halogen include alkoxy groupwhich may be substituted by halogen and alkylthio groups which may besubstituted for by halogen, resulting from binding of either theabove-exemplified alkyl group or such alkyl group substituted forhalogen and either an oxygen atom or a sulfur atom, respectively.

Examples of the optionally substituted alkoxy group includestraight-chain or branched alkoxy group having 1 to 6 carbon atoms orsuch alkoxy group substituted by 1 to 5 of the above-mentioned halogenatoms. Specifically, commonly used alkoxy group include methoxy,difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy,propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy,sec-butoxy, pentoxy and hexyloxy. Preferably used are straight-chain orbranched alkoxy groups having 1 to 4 carbon atoms such as methoxy,difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy,propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy andsec-butoxy, or such alkoxy group substituted for by 1 to 3 of theabove-mentioned halogen atoms.

Examples of the optionally substituted alkylthio group includestraight-chain or branched alkylthio group having 1 to 6 carbon atoms orsuch alkylthio group substituted for by 1 to 5 of the above-mentionedhalogen atoms. Specifically, commonly used alkylthio groups includemethylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,pentylthio and hexylthio. Preferably used are straight-chain or branchedalkylthio groups having 1 to 4 carbon atoms such as methylthio,difluoromethylthio, trifluoromethylthio, ethylthio, propylthio,isopropylthio, butylthio and 4,4,4-trifluorobutylthio, or such alkylthiogroups substituted for by 1 to 3 of the above-mentioned halogen atoms.

Preferable substituents on ring A and B include halogen (e.g. fluoro,chloro, bromo, etc.), optionally halogenated C₁₋₄ alkyl (e.g. methyl,chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl,2-bromoethyl, 2,2,2-trifluoroethyl, propyl, 3,3,3-trifluropropyl,isopropyl, 2-trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl,isobutyl, sec-butyl, tert-butyl, etc.), optionally halogenated C₁₋₄alkoxy (e.g. methoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, etc.), optionallysubstituted C₁₋₄ alkylthio (e.g. methylthio, difluoromethylthio,trifluoromethylthio, ethylthio, propylthio, isopropylthio, buthylthio,4,4,4-trifluorobuthylthio, etc.), C₁₋₃ acyloxy (e.g. formyloxy, acetoxy,propionyloxy, etc.), hydroxyl, amino, mono-or di-C₁₋₄ alkylamino (e.g.methylamino, ethylamino, propylamino, dimethylamino, diethylamino,etc.), carboxyl and C₁₋₄ alkoxy-carbonyl (e.g. methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, etc.).

More preferable substituents on ring A and B include halogen (e.g.fluoro, chloro, bromo, etc.), optionally halogenated C₁₋₄ alkyl (e.g.methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, propyl,3,3,3-trifluoropropyl, isopropyl, 2-trifluoromethylethyl, buthyl,4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, etc.), optionallyhalogenated C₁₋₄ alkoxy (e.g. methoxy, difluoromethoxy,trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy,butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, etc.), hydroxyl,amino, mono- or di- C₁₋₄ alkylamino (e.g. methylamino, ethylamino,propylamino, dimethylamino, diethylamino, etc.) and C₁₋₃ acyloxy (e.g.formyloxy, acetoxy, propionyloxy, etc.).

Specifically more preferable substituents on ring A and B includehalogen (e.g. fluoro, chloro, bromo, etc.), optionally halogenated C₁₋₄alkyl (e.g. methyl, chloromethyl, difluoromethyl, trichloromethyl,trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, propyl,3,3,3-trifluoropropyl, isopropyl, 2-trifluoromethylethyl, buthyl,4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, etc.), optionallyhalogenated C₁₋₄ alkoxy (e.g. methoxy, difluoromethoxy,trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy,butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, etc.).

The substituent(s) for rings A and B may be located at any position onthe ring. When two or more substituents are present, they may beidentical or not, the number of substituents being 1 to 4, preferably 1to 3, more preferably 1 or 2. Also, the adjacent carbons on ring A or Bmay bind with a group represented by --(CH₂)l-- (l represents an integerof from 3 to 5) to form a 5- to 7-membered ring.

I). Some Examples of Ring A and B

Ring A is preferably a benzene ring which may be substituted by one tofour substituents selected from the group consisting of halogen (e.g.,fluorine, chlorine, bromine, etc.), optionally halogenated C₁₋₄ alkylgroup (e.g., methyl, ethyl, isopropyl, trifluoromethyl etc.) andoptionally halogenated C₁₋₄ alkoxy group (e.g., methoxytrifluoromethoxy, ethoxy, etc.), specifically a benzene ring which maybe substituted and which is represented by formula A!: ##STR25## whereinA¹, A² and A³, whether identical or not, independently represent ahydrogen, a halogen (e.g., fluorine, chlorine, etc.), an optionallyhalogenated C₁₋₄ alkyl group (e.g., methyl, trifluoromethyl, ethyl,isopropyl, etc.) or an optionally halogenated C₁₋₄ alkoxy group (e.g.,methoxy, trifluoromethoxy, ethoxy, etc.). More preferably, for example,there may be used benzene ring which may be substituted and which isrepresented by the above formula A! wherein:

(1) A¹, A², and A³ are all hydrogen,

(2) A¹ and A² are both hydrogen, A³ being a halogen (e.g. fluorine,chlorine, etc.), an optionally halogenated C₁₋₄ alkyl group(e.g. methyl,trifluoromethyl, ethyl, etc.) or an optionally halogenated C₁₋₄ alkoxygroup (e.g. methoxy, trifluoromethoxy, ethoxy, etc.),

(3) A¹ is hydrogen, A² and A³, whether identical or not, beingindependently a halogen (e.g. fluorine, chlorine), a C₁₋₄ alkyl group(e.g. methyl, ethyl, etc.) or a C₁₋₄ alkoxy group (e.g. methoxy, ethoxy,etc.), or

(4) A² is hydrogen, A¹ and A³, whether identical or not, beingindependently a C₁₋₄ alkyl group (e.g. methyl, ethyl, etc.).

More preferably for ring A, for example, there may be used benzene ringswhich may be substituted and which is represented by the above formulaA! wherein:

(a) A¹, A² and A³ are all hydrogen,

(b) A¹ and A² are both hydrogen, A³ being chlorine, a methyl, ethyl,isopropyl, methoxy or trifluoromethyl group,

(c) A¹ is hydrogen, A² and A³ being both a methyl or methoxy group, or

(d) A² is hydrogen, A¹ and A³ being both a methyl group.

Ring B is preferably a benzene ring which may be substituted by one tofour substituents selected from the group consisting of a halogen (e.g.,fluorine, chlorine, etc.), an optionally halogenated C₁₋₄ alkyl group(e.g., methyl, trifluoromthyl, ethyl etc.) and, an optionallyhalogenated C₁₋₄ alkoxy group (e.g., methoxy, trifluoromethoxy, ethoxyetc.), specifically a benzene ring which may be substituted and which isrepresented by formula B!: ##STR26## wherein B¹, B² and B³, whetheridentical or not, independently represent hydrogen, a halogen (e.g.,fluorine, chlorine, etc.), an optionally halogenated C₁₋₄ alkyl group(e.g., methyl, trifluoromethoxy, ethyl, etc.) or an optionallyhalogenated C₁₋₄ alkoxy group (e.g., methoxy, trifluoromethoxy ethoxy,etc.). More preferably, for example, there may be used benzene ringwhich may be substituted and which is represented by the above formulaB! wherein:

(1) B¹, B² and B³ are all hydrogen,

(2) B¹ is halogen (e.g. fluorine, chlorine, etc.), an optionallyhalogenated C₁₋₄ alkyl group (e.g. methyl, trifluoromethyl, ethyl, etc.)or an optionally halogenated C₁₋₄ alkoxy group (e.g. methoxy,trifluoromethoxy, ethoxy, etc.), B² and B³ being both hydrogen,

(3) B¹ is hydrogen, B² and B³, whether identical or not, beingindependently an optionally halogenated C₁₋₄ alkoxy group (e.g. methoxy,trifluoromethoxy, ethoxy, etc.), or

(4) B¹, B² and B³, whether identical or not, are independently a C₁₋₄alkoxy group (e.g. methoxy, ethoxy, etc.).

More preferably for ring B, for example, there may be used benzene ringswhich may be substituted for and which is represented by the aboveformula B! wherein:

(a) B¹, B² and B³ are all hydrogen,

(b) B¹ is chlorine, fluorine, a methyl, trifluoromethyl or methoxygroup, B² and B³ being both hydrogen,

(c) B¹ is hydrogen, B² and B³ being both a methoxy group, or

(d) B¹, B² and B³ are all a methoxy group.

II). Other Examples of Ring A and B

Referring to ring A, concrete examples of the moiety ##STR27## includegroups of the formula: ##STR28## where A⁴, A⁵ and A⁶ are the same ordifferent and each means a halogen atom such as fluoro, chloro, etc., anoptionally halogenated C₁₋₄ alkyl group such as methyl, ethyl, isopropyltrifluoromethyl, etc., or an optionally halogenated C₁₋₄ alkoxy groupsuch as methoxy, trifluoromethoxy, ethoxy, etc.

Preferred examples of ring A are groups of the formula: ##STR29##wherein A⁷ and A⁸ represents a halogen atom (e.g. fluorine, chlorine,etc.), an optionally halogenated C₁₋₄ alkyl group (e.g., methyl,trifluoromethyl, ethyl, etc.). More preferably, for example, there maybe used benzene ring which may be substituted and which is representedby the above formula wherein

(1) A⁴ is a halogen (e.g. fluorine, chlorine, etc.) or an optionallyhalogenated C₁₋₄ alkyl group (e.g., methyl, trifluoromethyl, ethyl,propyl)

(2) A⁵ and A⁶ are an optionally halogenated a C₁₋₄ alkyl group (e.g.,methyl, trifluoromethyl, ethyl, etc.) or a C₁₋₄ alkoxy group (e.g.,methoxy, ethoxy, etc.),

(3) A⁷ and A⁸ are a C₁₋₄ alkyl group (e.g. methyl, ethyl, etc.),

(4) A⁴ is a halogen (e.g., fluorine, chlorine, etc.),

(5) A⁵ and A⁶ are a C₁₋₄ alkoxy group (e.g. methoxy, ethoxy, etc.),

Referring to ring B, concrete examples of the moiety ##STR30## includegroups of the formula: ##STR31## where in B⁴, B⁵, B⁶, B⁷, B⁸ and B⁹ arethe same or different and each means a halogen atom such as chloro,fluoro, etc., an optionally halogenated C₁₋₄ alkyl group such as methyl,trifluoromethyl, ethyl, etc., or an optionally halogenated C₁₋₄ alkoxygroup such as methoxy trifluoromethoxy, ethoxy, etc.

Preferred examples of the ring B are groups of the formula: ##STR32##wherein B⁴, B⁵ and B⁶ is the same meaning hereinbefore. Particularlypreferred examples are groups of the formula: ##STR33## wherein B¹⁰ isan optionally halogenated C₁₋₄ alkyl group (e.g., methyl,trifluoromethyl, ethyl, etc.).

More preferably, for example, there may be used benzene rings which maybe substituted and which is represented by the above formula wherein:

(1) B⁴ is a halogen (e.g., fluoro, chrolo etc.) or an optionallyhalogenated C₁₋₄ alkyl group (e.g., methyl, trifluoromethyl, ethyl,etc.)

(2) B⁵ and B⁶, whether identical or not, being independently anoptionally halogenated C₁₋₄ alkyl group (e.g., methyl, trifluoromethyl,ethyl, etc.).

(3) B⁴ is an optionally halogenated C₁₋₄ alkoxy group (e.g., methoxy,trifluoromethoxy, ethoxy, etc.)

(4) B⁵ and B⁶, whether identical or not, being independently anoptionally halogenated C₁₋₄ alkoxy group (e.g., methoxy,trifluoromethoxy, ethoxy, etc.)

With respect to the above formulas, R¹ represents a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedhydroxyl group or an optionally substituted amino group.

R² and R^(2a) independently represent a hydrogen atom or an optionallysubstituted hydrocarbon group.

R³ represents a hydrogen atom, a halogen atom, an optionally substitutedhydrocarbon group, an optionally substituted amino group, a substitutedhydroxyl group or a mercapto group substituted by an optionallysubstituted hydrocarbon group.

R⁴ represents a hydrogen atom, a hydroxyl group or an optionallysubstituted hydrocarbon group.

R⁵ represents a hydrogen atom or an optionally substituted hydrocarbongroup.

The hydrocarbon group described hereinabove include alkyl group, alkenylgroup, alkynyl group, cycloalkyl group and aryl group. etc.

Preferable examples of hydrocarbon group are an alkyl group, acycloalkyl group and an aryl group, and more preferable examples are analkyl group.

The alkyl group includes a straight-chain or branched alkyl group having1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc., preferably astraight-chain or branched alkyl group having 1 to 4 carbon atoms suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl ortert-butyl, etc.

The alkenyl group includes alkenyl group having 2 to 6 carbon atoms suchas ethenyl, propenyl, isopropenyl, butenyl, isobutenyl or sec-butenyl,etc., preferably an alkenyl group having 2 to 4 carbon atoms such asethenyl, propenyl or isopropenyl, etc.

The alkynyl group includes alkynyl group having 2 to 6 carbon atoms suchas ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, etc., orsec-butynyl, etc., preferably an alkynyl group having 2 to 4 carbonatoms such as ethynyl, propynyl or isopropynyl, etc.

The cycloalkyl group includes a C₃₋₈ cycloalkyl group such ascyclopropyl, cyclobutyl, cyclopentyl, etc., or cyclohexyl, preferably aC₃₋₆ cycloalkyl group such as cyclopropyl or cyclobutyl, etc.

The aryl group includes aryl group having 6 to 14 carbon atoms such asphenyl, naphthyl, anthryl or phenanthryl etc., preferably an aryl grouphaving 6 to 10 carbon atoms such as phenyl or naphthyl, and morepreferably a phenyl group.

Examples of the substituent for the optionally substituted hydrocarbongroup include (i) halogen, (ii) cycloalkyl group, (iii) aryl group, (iv)amino group which may have an alkyl, alkenyl, cycloalkyl or aryl groupas a substituent, (v) hydroxyl group, (vi) optionally halogenated alkoxygroup (vii) acyl group, (viii) acyloxy group, (ix) cyano group, (x)optionally protected carboxyl group (xi) carbamoyl groups, (xii)mercapto group, (xiii) alkylthio group, (xiv) sulfo group and (xv)alkylsulfonyl group.

The optionally substituted hydrocarbon group may be substituted for by 1to 4, preferably 1 or 2 of the above-mentioned substituents, whetheridentical or not.

The halogen atom is exemplified by fluorine, chlorine, bromine andiodine, preferably fluorine and chlorine. The cycloalkyl group isexemplified by C₃₋₆ cycloalkyl group such as cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. The aryl group is exemplified by C₆₋₁₀ arylgroup such as phenyl and naphthyl, and preferably a phenyl. With respectto the amino group which may have an alkyl, alkenyl, cycloalkyl or arylgroup as a substituent, the alkyl group is exemplified by C₁₋₄ alkylgroups such as methyl, ethyl, propyl and isopropyl; the alkenyl group isexemplified by C₂₋₄ alkenyl group such as ethenyl, propenyl, isopropenyland butenyl; the cycloalkyl group is exemplified by C₃₋₆ cycloalkylgroup such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; thearyl group is exemplified by C₆₋₁₀ aryl group such as phenyl andnaphthyl, preferably a phenyl. Said amino group is preferably an aminogroup which may be substituted by one to three C₁₋₄ alkyl groups (e.g.,methyl, ethyl, etc.), such as amino, methylamino, ethylamino,dimethylamino, trimethylamino and diethylamino. The optionallyhalogenated alkoxy group is exemplified by C₁₋₄ alkoxy group such asmethoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy and sec-butoxy, or such alkoxy groupsubstituted for by 1 to 3 halogen atoms (e.g., fluorine, chlorine). Theacyl group is a C₁₋₄ acyl group such as formyl, acetyl, propionyl,butyryl or isobutyryl. The acyloxy group is a C₁₋₄ acyloxy group such asformyloxy, acetyloxy, propionyloxy, butyryloxy or isobutyryloxy. Theprotecting group for the optionally protected carboxyl group isexemplified by C₁₋₄ alkyl groups such as methyl, ethyl and t-butylgroups and C₇₋₁₁ aralkyl group such as benzyl. The alkylthio group is aC₁₋₄ alkylthio group such as methylthio, ethylthio, propylthio,isopropylthio or butylthio. The alkylsulfonyl group is a C₁₋₄alkylsulfonyl group such as a methylsulfonyl, ethylsulfonyl,propylsulfonyl, isopropylsulfonyl or butylsulfonyl group.

Preferable example of substituents for the optionally substitutedhydrocarbon group include (i) halogen, (ii) cycloalkyl group, (iii) arylgroup, (iv) amino group which may have an alkyl, alkenyl, cycloalkyl oraryl group as a substituent, (v) hydroxyl group, (vi) optionallyhalogenated alkoxy group (vii) acyl group, (viii) acyloxy group, (ix)cyano group, (x) optionally protected carboxyl group and (xi) carbamoylgroup, and the term of (i) to (xi) is the same meaning describedhereinabove.

More preferable examples of the substituent include the follows (1) to(3):

(1) (i) C₃₋₆ cycloalkyl group such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and so on,

(ii) C₆₋₁₀ aryl group such as phenyl, naphthyl and so on,

(iii) amino group which may be substituted by one to three C₁₋₄ alkylgroups, such as amino, methylamino, ethylamino, dimethylamino,trimethylamino, diethylamino and so on,

(iv) carboxyl group which may be substituted by a C₁₋₄ alkyl, such ascarboxyl, carboxylmethyl, carboxylethyl and so on,

(2) halogen such as fuluoro, chloro, buromo and so on,

(3) (i) carboxyl, (ii) C₁₋₄ alkyl-carbonyl such as carboxymethyl,carboxyethyl, etc. or (iii) mono, di- or tri C₁₋₄ alkylamino such asamino, methylamino, dimethylamino, trimethylamino, etc.

Further, the hydrocarbon group are also preferable a C₁₋₆ alkyl group,C₃₋₆ cycloalkyl group, a C₃₋₆ cycloalkyl-C₁₋₄ alkyl group, preferably aC₁₋₆ alkyl group. The C₁₋₆ alkyl group mentioned above includes methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, neopentyl, hexyl and so on. Preferred are C₁₋₄ alkyl groups suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl and so on. The C₃₋₆ cycloalkyl group may for example becyclopropyl, cyclopentyl or cyclohexyl and so on. The C₃₋₆cycloalkyl-C₁₋₄ alkyl group includes, among others, cyclopropylmethyland cyclopropylethyl and so on.

The substituent group(s) of the hydrocarbon group include halogen atom(e.g. fluoro, chloro, bromo, iodo, etc.), nitro, cyano, hydroxyl, C₁₋₄alkoxy group (e.g. methoxy, ethoxy, propyloxy, butyloxy, isopropyloxy,etc.), C₁₋₄ alkylthio group (e.g. methylthio, ethylthio, propylthioetc.), amino, mono-, di or tri-C₁₋₄ alkylamino group (e.g. methylamino,ethylamino, propylamino, dimethylamino, diethylamino, trimethylaminoetc.), cyclic amino group (e.g. 5- to 9-membered cyclic amino groupwhich may contain 1 to 3 hetero-atoms such as oxygen and sulfur inaddition to nitrogen as ring-constituent members, such as pyrrolidino,piperidino, morpholino, etc.), C₁₋₄ alkyl-carbonylamino group (e.g.acetylamino, propionylamino, butyrylamino, etc.), C₁₋₄alkylsulfonylamino group (e.g. methylsulfonylamino, ethylsulfonylamino,etc.), C₁₋₄ alkoxy-carbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, etc.), carboxyl, C₁₋₆ alkyl-carbonyl group (e.g.methylcarbonyl, ethylcarbonyl, propylcarbonyl, etc.), carbamoyl, mono-or di-C₁₋₄ alkyl-carbamoyl group (e.g. methylcarbamoyl, ethylcarbamoyl,etc.), C₁₋₆ alkylsulfonyl group (e.g. methylsulfonyl, ethylsulfonyl,propylsulfonyl, etc.), phenyl, C₁₋₃ alkoxyphenyl (e.g. methoxyphenyl,ethoxyphenyl, etc.) and so on. 1 to 5, preferably 1 or 2, species ofthese substituents may be present.

Preferable examples of substituents hereinabove include a hydroxylgroup, a C₁₋₄ alkoxy group (e.g. methoxy, ethoxy, propoxy, etc.), anamino group, a mono- or di-C₁₋₄ alkylamino group (e.g. methylamino,ethylamino, dimethylamino, diethylamino, etc.), a C₁₋₄ alkoxy-carbonylgroup (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), acarboxyl group, a carbamoyl group, a phenyl group and so on.

Specially preferable examples of substituents are a carboxyl group and acarbamoyl group.

The optionally substituted hydroxyl group described hereinabove includesa hydroxyl group, a C₁₋₄ alkoxy group (e.g. methoxy, ethoxy, propoxy,isopropoxy, butoxy, t-butoxy, etc.), a C₆₋₁₀ aryloxy group (e.g.phenoxy, naphthyloxy, etc.), a C₁₋₄ alkyl-carbonyloxy (e.g. formyloxy,acethyoxy, propyonyloxy, etc.) and a C₆₋₁₀ aryl-carbonyloxy group (e.g.benzoyloxy, naphthoyloxy, etc.).

Preferable examples are a hydroxyl group and a C₁₋₄ alkoxy group (e.g.methoxy, ethoxy, propoxy, isopropoxy, etc.)

These groups may be substituted, and the substituents include the sameone as the substituents of the hydrocarbon group hereinabove, preferablya halogen atom (e.g. fluoro, chloro, bromo, etc.).

The substituted hydroxyl group include a C₁₋₄ alkoxy group (e.g.methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, etc.), a C₆₋₁₀aryloxy group (e.g. phenoxy, naphthyloxy, etc.), a C₁₋₄alkyl-carbonyloxy (e.g. formyloxy, acethyoxy, propyonyloxy, etc.), aC₆₋₁₀ aryl-carbonyloxy group (e.g. benzoyloxy, naphthoyloxy, etc.).Preferable examples are a C₁₋₄ alkoxy group (e.g. methoxy, ethoxy,propoxy, etc.). The substituents of a substituted hydroxyl group includethe same one as the substituents of the hydrocarbon group hereinaboveand so on, preferably a halogen atom (e.g. fluoro, chloro, bromo, etc.).

The halogen atom includes a fluorine, a chlorine, a bromine and so on.

The optionally substituted amino group includes an amino group which maybe substituted by one to three substituents selected from the groupconsisting of (i) C₁₋₄ alkyl group (e.g. methyl, ethyl, propyl,isopropyl, etc.), (ii) C₁₋₄ alkyl-carbonyl (e.g. acetyl, propyonyl,butynyl, etc.), (iii) C₁₋₄ alkoxy-carbonyl group (e.g. methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, etc.), (iv) halogen (e.g. fluoro,chloro, etc.), (v) phenyl, (vi) C₁₋₄ alkyl-phenyl (e.g. 4-methylphenyl,3-methylphenyl, 2-methylphenyl, etc.), (vii) halogenated phenyl (e.g.4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, etc.) and (viii) C₁₋₄alkoxy-phenyl (e.g. 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl,etc.) and so on.

Preferable examples of an optionally substituted amino group include anamino group or a mono- or di-C₁₋₄ alkylamino group (e.g. methylamino,ethylamino, propylamino, dimethylamino, diethylamino, etc.).

The optionally substituted hydrocarbon group of the mercapto groupsubstituted by an optionally substituted hydrocarbon group are used thesame one as defined hereinabove. Preferable examples of the mercaptogroup substituted by an optionally substituted hydrocarbon group includea C₁₋₄ alkylthio (e.g. methylthio, ethylthio, propylthio, etc.), and soon.

Preferable examples of R¹ include (i) a hydrogen atom and (ii) a C₁₋₄alkyl group (e.g. methyl, ethyl, propyl, etc.) which may be substitutedby (a) a mono-, di- or tri- C₁₋₄ alkylamino group (e.g. methylamino,ethylamino, propylamino, dimethylamino, trimethylamino, etc.), (b) aC₁₋₄ alkoxy-carbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, etc.), (c) a carbamoyl group or (d) a carboxyl group.

More preferable examples of R¹ are a C₁₋₄ alkyl group (e.g. methyl,ethyl, propyl, etc.).

Preferable example of R² and R^(2a) is a hydrogen atom

Preferable examples of R³ include (i) a hydrogen atom, (ii) a halogenatom (e.g. fluoro, chloro, bromo, etc.), a C₁₋₄ alkoxy group (e.g.methoxy, ethoxy, propoxy, etc.), a C₁₋₄ alkyl group (e.g. methyl, ethyl,propyl, etc.), a C₁₋₄ alkylthio group (e.g. methylthio, ethylthio, etc.)and a mono- or di-C₁₋₄ alkylamino, (e.g. methylamino, ethylamino,dimethylamino, diethylamino, etc.); and (iii) a halogen atom (e.g.fluoro, chloro etc.) and mono-C₁₋₄ alkylamino (e.g. methylamino,ethylamino, etc.).

Preferable examples of R⁴ include (i) a hydrogen atom and (ii) a C₁₋₄alkyl group (e.g. methyl, ethyl, propyl, etc.), a hydroxyl group andhalogen atom (e.g. fluoro, chloro, etc.).

Preferable examples of R⁵ include (i) a hydrogen atom and (ii) a C₁₋₄alkyl group (e.g. methyl, ethyl, propyl, etc.).

With respect to the above formula, either X or Y represents --NR¹ -- (R¹represents a hydrogen atom, an optionally substituted hydrocarbon group,an optionally substituted hydroxyl group or an optionally substitutedamino group), --O-- or --S--, the other representing --CO--, --CS-- or--C(R²)R^(2a) -- (R² and R^(2a) independently represent a hydrogen atomor an optionally substituted hydrocarbon group), or ether X or Yrepresents --N═, the other representing ═CR³ -- (R³ represents ahydrogen atom, a halogen atom, an optionally substituted hydrocarbongroup, an optionally substituted amino group, a substituted hydroxylgroup or a mercapto group substituted by an optionally substitutedhydrocarbon group).

Preferable examples of X and Y (--X--Y--) include the following:

(i) either X or Y represents --NR¹ -- or --O--, the other representing--CO--, --CS-- or --C(R²)R^(2a) -- (R¹, R² and R^(2a) represent the samemeanings as defined hereinabove),

(ii) either X or Y represents --N═, the other representing ═CR³ -- (R³represents the same meaning as defined hereinabove),

(iii) --NR¹ --CO--, --NR¹ --CH₂ --, --CONR¹ --, --O--CO--, --CO--O--,--N═CR³ -- and --CR³ ═N-- (R¹ and R³ represents the same meanings asdefined hereinabove),

(iv) --N(CH₃)--CO--, --N(C₂ H₅)--CO--, --N(CH₃)--CH₂ --, --N(C₂H₅)--CH₂, --CO-- N(CH₃), --CO--N(C₂ H₅)--, --O--CO--, --CO--O----N═CH--, --N═C(CH₃)--, --N═C(OCH₃)--, --N═CCl, --N═C(NHCH₃)--,--CH═N--, --C(Cl)═N--, --C(OCH₃)═N-- and --C(NHCH₃)═C--,

(v) --CONR¹ -- and --NR¹ --CO-- (R¹ represents the same meanings asdefined hereinabove)

(vi) --O--CO--

(vii) --CO--O--

(viii) --NR¹ --C(R²)R^(2a) -- and --C(R²)R^(2a) --NR¹ -- (R¹, R² andR^(2a) represent the same meaning as defined hereinabove),

(ix) --N═CR³ -- (R³ represents the same meaning as defined hereinabove),

(x) --CS--NR¹ -- (R¹ represents the same meaning as definedhereinabove).

With respect to the above formula, ........ represents a single ordouble bond; (i) when ........ adjacent to Z is a single bond, Zrepresents ##STR34## (R⁴ represents a hydrogen atom, a hydroxyl group oran optionally substituted hydrocarbon group) or a nitrogen atom, or (ii)when ........ adjacent to Z is a double bond, Z represents a carbonatom.

Preferable examples of ........ and Z include the following:

i) ........ on the ring A is a double bond,

ii) ........ on the ring C is a single bond, and Z is ##STR35## (R⁴represents the same meanings as defined hereinabove), iii) ........ onthe ring C is a single bond, and Z is a nitrogen atom,

iv) ........ on the ring C is a double bond, and Z is a carbon atom.

With respect to the above formula, D represent a C₁₋₃ alkylene groupwhich may be substituted by an oxo or thioxo group, or D and R¹, takentogether, may form 5- to 7-membered ring which may be substituted by anoxo or thioxo group.

The C₁₋₃ alkylene group includes --CH₂ --, --CH₂ CH₂ --, --CH₂ CH₂ CH₂-- and --CH(CH₃)--CH₂ -- and so on.

D includes --CO--, --CS--, --CH₂ --, --CH₂ CH₂ --, --CH₂ CO--, --CH₂CS--, --CH₂ CH₂ CO-- and --CH₂ CH₂ CS-- and so on.

Preferable examples of D include

(i) a C₁₋₃ alkylene group which may be substituted by an oxo group, (ii)--CH₂ --, --CH₂ CH₂ --, --CO--, --CH₂ CO-- and --CH₂ CH₂ CO--, (iii)--CO--, (iv) --CH₂ CO-- and --CH₂ CH₂ CO--, and (v) --CH₂ -- and --CH₂CH₂ --.

Preferable examples of the compounds (I) and (I') wherein the 5- to7-membered ring is formed by D and Y include compounds of the formula:##STR36## wherein ring K^(a) may be substituted by an oxo or thioxogroup; h represents an integer of 3 to 5; and the other symbolsrepresent the same meaning as defined hereinabove, more preferably thecompounds of the formula: ##STR37## wherein ring K^(b) may besubstituted by an oxo group; and the other symbols represent the samemeaning as defined hereinabove.

With respect to the above formula, E represents --NR⁵ -- (R⁵ representsa hydrogen atom or an optionally substituted hydrocarbon group), --O--or --S(O)n-- (n is 0, 1 or 2), or R⁵ and Y, taken together, may form 5-to 7-membered ring which may be substituted by an oxo or thioxo group.

Preferable examples of the compounds (I) and (I') wherein the 5- to7-membered ring combined R⁵ and Y include also compounds of the formula:##STR38## wherein the ring K^(c) may be substituted by an oxo or thioxogroup; i represents an integer of 1 to 3, the total carbon number of Eand --(CH₂)i-- being 3 to 5; and the other symbols represent the samemeanings as defined hereinabove, preferably compound of the formula:##STR39## wherein E^(a) and M represent --CH₂ -- or --CO--; and theother symbols represent the same meanings as defined hereinabove.

Preferable examples of E include --NR⁵ -- (R5 represents the samemeaning as defined hereinabove) and --O--, more preferably --NR⁵ -- (R⁵represents the same meaning as defined hereinabove).

Preferable examples of G include the following:

(i) a bond,

(ii) a C₁₋₃ alkylene group such as methylene, ethylene, propylene, etc.

Preferable examples of D, E and G include the follow:

(i) D is --CO--; E is --NR⁵ -- (R⁵ represents the same meaning asdefined hereinabove); G is --CH₂ -- or --CH₂ CH₂ --,

(ii) D is --CO--; E is --NR⁵ -- (R⁵ represents the same meaning asdefined hereinabove); G is a bond,

(iii) D is --CH₂ CO-- or --CH₂ CH₂ CO--; E is --NR⁵ -- (R⁵ represent thesame meaning as defined herein); G is a bond,

(iv) D is --CH₂ CO-- or --CH₂ CH₂ CO--; E is --NR⁵ -- (R⁵ represent thesame meaning as defined hereinabobe); G is --CH₂ -- or --CH₂ CH₂ --,

(v) D is --CH₂ -- or --CH₂ CH₂ --; E is --O--; G is --CH₂ -- or --CH₂CH₂ --,

(vi) D is --CH₂ -- or --CH₂ CH₂ --; E is --NR⁵ -- (R⁵ represent the samemeaning as defined herein); G is --CH₂ -- or --CH₂ CH₂ --,

(vii) D is --CH₂ -- or --CH₂ CH₂ --; E is --S-- or --SO--; G is --CH₂ --or --CH₂ CH₂ --.

In the above formula, Ar represents an optionally substituted aryl groupor an optionally substituted heterocyclic group. The aryl group in the"optionally substituted aryl group" represented by Ar, is preferably aC₆₋₁₀ aryl group such as phenyl or naphthyl or the like, with greaterpreference given to a phenyl group etc. The aryl group represented by Armay have one to five substituents, preferably one to three substituents,whether identical or not. These substituents may be located at anyposition of the ring. Such substituents include an optionallyhalogenated C₁₋₄ alkyl group (e.g., methyl, chloromethyl,difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,2,2,2-trifluoroethyl, propyl, 3,3,3-trifluoropropyl, butyl), C₁₋₄ alkylgroup substituted by an amino group (e.g., aminomethyl, 2-aminoethyl,etc.), C₁₋₄ alkyl group substituted by a mono- or di-C₁₋₄ alkylaminogroup (e.g., methylaminomethyl, dimethyl-aminomethyl), C₁₋₄ alkyl groupsubstituted by a carboxyl group (e.g., carboxymethyl, carboxyethyl),C₁₋₄ alkyl group substituted by a C₁₋₄ alkoxycarbonyl group (e.g.,methoxycarbonylethyl, ethoxycarbonylethyl), C₁₋₄ alkyl group substitutedby a hydroxyl group (e.g., hydroxymethyl, hydroxyethyl), C₁₋₄ alkylgroup substituted by a C₁₋₄ alkoxycarbonyl group (e.g., methoxymethyl,methoxyethyl, ethoxyethyl), C₃₋₆ cycloalkyl group (e.g., cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl), halogen atom (e.g., fluorine,chlorine, bromine, iodine), nitro group, cyano group, hydroxyl group,optionally halogenated C₁₋₄ alkoxy group (e.g., methoxy,difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy,propyloxy, butyloxy, isopropyloxy), optionally halogenated C₁₋₄alkylthio group (e.g., methylthio, difluoromethylthio,trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio),amino group, mono- or di-C₁₋₄ alkylamino group (e.g., methylamino,ethylamino, propylamino, dimethylamino, diethylamino), cyclic aminogroup (e.g., 5- to 9-membered cyclic amino group which may have one tothree hetero atoms such as oxygen and sulfur atoms in addition tonitrogen atoms, specifically pyrrolidino, piperidino, morpholino), C₁₋₄alkylcarbonylamino group (e.g., acetylamino, propionylamino,butylylamino), aminocarbonyloxy group, mono- or di- C₁₋₄alkylaminocarbonyloxy group (e.g., methylaminocarbonyloxy,ethylaminocarbonyloxy, dimethylaminocarbonyloxy,diethylaminocarbonyloxy), C₁₋₄ alkylsulfonylamino group (e.g.,methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino), C₁₋₄alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isobutoxycarbonyl), benzyloxycarbonyl group, carboxylgroup, C₁₋₆ alkyl-carbonyl group (e.g., methylcarbonyl, ethylcarbonyl,butylcarbonyl), C₃₋₆ cycloalkyl-carbonyl group (e.g.,cyclohexylcarbonyl), carbamoyl group, mono- or di-C₁₋₄ alkylcarbamoylgroup (e.g., methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl,butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl) and C₁₋₆alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl,propylsulfonyl). In addition, the below-described "optionallysubstituted heterocyclic group," represented by Ar, may be used as suchas a substituent for the aryl group. This optionally substitutedheterocyclic group is exemplified by 5- or 6-membered aromaticmono-heterocyclic group (e.g., furyl, thienyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl) which may be substituted by one to threesubstituents such as those selected from the group consisting ofoptionally halogenated C₁₋₄ alkyl group (e.g., methyl, chloromethyl,difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,2,2,2-trifluoroethyl, propyl, 3,3,3-trifluoropropyl, butyl), C₃₋₆cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl), halogen atom (e.g., fluorine, chlorine, bromine, iodine),hydroxyl group, optionally halogenated C₁₋₄ alkoxy group (e.g., methoxy,difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy,propyloxy, butyloxy, isopropyloxy), optionally halogenated C₁₋₄alkylthio group (e.g., methylthio, difluoromethylthio,trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio),amino group, mono- or di-C₁₋₄ alkylamino group (e.g., methylamino,ethylamino, propylamino, dimethylamino, diethylamino), C₁₋₄alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isobutoxycarbonyl), carboxyl group and C₁₋₆alkyl-carbonyl group (e.g., methylcarbonyl, ethylcarbonyl,butylcarbonyl).

Preferable examples of substituents of Ar include optionally halogenatedC₁₋₄ alkyl group (e.g., methyl, chloromethyl, difluoromethyl,trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,2,2,2-trifluoroethyl, propyl, isopropyl, 3,3,3-trifluoropropyl), halogenatom (e.g., fluorine, chlorine, bromine), nitro group, hydroxyl group,optionally halogenated C₁₋₄ alkoxy group (e.g., methoxy,difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy), aminogroup, C₁₋₄ alkyl group substituted by a mono-or di-C₁₋₄ alkylaminogroup (e.g., methylaminomethyl, dimethylaminomethyl, 2-methylaminoethyl,2-dimethylaminoethyl.), mono- or di-C₁₋₄ alkylamino group (e.g.,methylamino, ethylamino, dimethylamino, diethylamino), C₁₋₄alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl), carboxylgroup and carbamoyl group, and optionally halogenated C₁₋₄ alkyl group(e.g., methyl, chloromethyl, difluoromethyl, trichloromethyl,trifluoromethyl, ethyl, 2-bromoethyl, propyl, isopropyl), halogen atom(e.g., fluorine, chlorine, bromine) and C₁₋₄ alkoxy group (e.g.,methoxy, ethoxy, propoxy) are commonly used.

The heterocyclic group in the "optionally substituted heterocyclicgroup," represented by Ar, is exemplified by 5- to 9-membered,preferably 5- or 6-membered aromatic heterocyclic group which may haveone to four, preferably one or two hetero atoms such as nitrogen, oxygenand sulfur atoms in addition to carbon atoms.

Such aromatic heterocyclic group include aromatic mono-heterocyclicgroup such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl and triazinyl and aromatic condensed heterocyclic group suchas benzofuranyl, isobenzofuranyl, benzo b!thienyl, indolyl, isoindolyl,1H-indazolyl, benzoimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl,benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl,isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,naphthylizinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl,β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl,phenazinyl, phenoxathinyl, thianthrenyl, phenatholidinyl,phenathololinyl, indolizinyl, pyrrolo 1,2-b!pyridazinyl, pyrazolo1,5-a!pyridyl, imidazo 1,2-a!pyridyl, imidazo 1,5-a!pyridyl, imidazo1,2-b!pyridazinyl, imidazo 1,2-a!pyrimidinyl, 1,2,4-triazolo4,3-a!pyridyl and 1,2,4-triazolo 4,3-b!pyridazinyl.

Preferable examples of the heterocyclic group include 5- or 6-memberedheterocyclic groups such as furyl, thienyl, pyrrolyl, oxazolyl,isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, quinolyl,isoquinolyl, thiazolyl, thiadiazolyl and thiophenyl, with greaterpreference given to furyl, thienyl, pyridyl, etc.

The substituent in the "optionally substituted heterocyclic group,"represented by Ar, is exemplified by optionally halogenated C₁₋₄ alkylgroup(e.g., methyl, chloromethyl, difluoromethyl, trichloromethyl,trifluoromethyl, ethyl, 2,2-dibromoethyl, 2,2,2-triflu-oroethyl, propyl,3,3,3-trifluoropropyl, butyl), C₃₋₆ cycloalkyl group (e.g., cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl), halogen atom (e.g., fluorine,chlorine, bromine, iodine), nitro group, cyano group, hydroxyl group,optionally halogenated C₁₋₄ alkoxy group (e.g., methoxy, fluoromethoxy,difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-triflu-oroethoxy,propyloxy, butyloxy, isopropyloxy), optionally halogenated C₁₋₄alkylthio group (e.g., methylthio, difluoromethylthio,trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio),amino group, mono- or di-C₁₋₄ alkylamino group (e.g., methylamino,ethylamino, propylamino, dimethylamino, diethylamino), cyclic aminogroup (e.g., 5- to 9-membered cyclic amino groups which may have one tothree hetero atoms such as oxygen and sulfur atoms in addition tonitrogen atoms, specifically pyrrolidino, piperidino, morpholino), C₁₋₄alkylcarbonylamino group (e.g., acetylamino, propionylamino,butylylamino), aminocarbonyloxy group, mono- or di-C₁₋₄alkylaminocarbonyloxy group (e.g., methylaminocarbony-loxy,ethylaminocarbonyloxy, dimethylaminocarbonyloxy,diethylaminocar-bonyloxy), C₁₋₄ alkylsulfonylamino group (e.g.,methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino), C₁₋₄alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isobutoxycarbonyl), carboxyl group, C₁₋₆ alkyl-carbonylgroup (e.g., methylcarbonyl, ethylcarbonyl, butylcarbonyl), C₃₋₆cycloalkyl-carbonyl group (e.g., cyclohexylcarbonyl), carbamoyl group,mono- or di-C₁₋₄ alkylcarbamoyl group (e.g., methylcarbamoyl,ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl,dibutylcarbamoyl), C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl,ethylsulfonyl, propylsulfonyl), C₃₋₆ cycloalkylsulfonyl group (e.g.,cyclopentylsulfonyl, cyclohexylsulfonyl), phenyl, naphthyl, phenoxy,benzoyl, phenoxycarbonyl, phenyl-C₁₋₄ alkylcarbamoyl, phenylcarbamoyl,phenyl-C₁₋₄ alkyl-carbonylamino, benzoylamino, phenyl-C₁₋₄alkylsulfonyl, phenylsulfonyl, phenyl-C₁₋₄ alkylsulfinyl, phenyl-C₁₋₄alkylsulfonylamino and phenylsulfonylamino group which may have one tofour substituents (the substituent for each phenyl group or naphthylgroup is exemplified by C₁₋₄ alkyl group such as methyl, ethyl, propyl,butyl and isopropyl, C₁₋₄ alkoxy group such as methoxy, ethoxy,n-propyloxy, i-propyloxy and n-butyloxy, halogen atom such as chlorine,bromine and iodine, hydroxyl group, benzyloxy group, amino group, mono-or di-C₁₋₄ alkylamino group as descried above, nitro group and C₁₋₆alkylcarbonyl group as described above); one to three selected fromthese substituents are used.

Of these substituents are preferred halogen atom (e.g., fluorine,chlorine, bromine), optionally halogenated C₁₋₄ alkyl group (e.g.,methyl, chloromethyl, difluoromethyl, trifluoromethyl, ethyl), C₃₋₆cycloalkyl group (e.g., cyclopropyl, cyclobutyl), hydroxyl group,optionally halogenated C₁₋₄ alkoxy group (e.g., methoxy,difluoromethoxy, trifluoromethoxy, ethoxy), optionally halogenated C₁₋₄alkylthio group (e.g., methylthio, ethylthio), amino group, mono- ordi-C₁₋₄ alkylamino group (e.g., methylamino, ethylamino, dimethylamino,diethylamino), C₁₋₄ alkoxy-carbonyl group (e.g., methoxycarbonyl,ethoxycarbonyl) and carboxyl group, with greater preference given tohalogen atom (e.g., fluorine, chlorine), C₁₋₄ alkyl group (e.g., methyl,ethyl), C₃₋₆ cycloalkyl group (e.g., cyclopropyl, cyclobutyl), hydroxylgroup, C₁₋₄ alkoxy group (e.g., methoxy, ethoxy) and carboxyl group,etc.

Ar is preferably a phenyl group which may have one to three substituentsselected from the group consisting of halogen atom (e.g., fluorine,chlorine), optionally halogenated C₁₋₄ alkyl group (e.g., methyl,difluoromethyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, propyl,isopropyl) and optionally halogenated C₁₋₄ alkoxy group (e.g., methoxy,difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy,propoxy, isopropoxy). Also preferred are 5- or 6-membered heterocyclicgroups (e.g., furyl, pyridyl, thienyl, thiazolyl, thiadiazolyl) whichhave one to three hetero atoms (e.g., nitrogen atoms, oxygen atoms,sulfur atoms) in addition to carbon atoms and which may be substitutedby optionally halogenated C₁₋₄ alkyl group (e.g., methyl,trifluoromethyl, ethyl), C₁₋₄ alkoxy group (e.g., methoxy, ethoxy,propoxy) or C₃₋₆ cycloalkyl group (e.g., cyclopropyl).

Ar is preferably a phenyl group which may be substituted by one to threesubstituents selected from the group consesting halogen (e.g., chlorine,fluorine), optionally halogenated C₁₋₄ alkyl group (e.g., methyl,trifluoromethyl ethyl, isopropyl), optionally halogenated C₁₋₄ alkoxygroup (e.g., methoxy, trifluoromethoxy, ethoxy), di-C₁₋₄ alkylaminogroup (e.g., dimethylamino), C₁₋₃ acyloxy group (e.g., acetoxy) andhydroxyl group, specifically a phenyl group which may be substituted forand which is represented by formula: ##STR40## wherein J¹, J² and J³,whether identical or not, independently represent hydrogen, a halogen(e.g., chlorine, fluorine), an optionally halogenated C₁₋₄ alkyl group(e.g., methyl, trifluoromethyl ethyl, isopropyl), an optionallyhalogenated C₁₋₄ alkoxy group (e.g., methoxy, trifluoromethoxy, ethoxy)or a di-C₁₋₄ alkylamino group (e.g., dimethylamino), or by formula:##STR41## wherein J⁴, J⁵ and J⁶, whether identical or not, independentlyrepresent hydrogen, an optionally halogenated C₁₋₄ alkyl group (e.g.,methyl, trifluoromethyl isopropyl, t-butyl), a C₁₋₃ acyloxy group (e.g.,acetoxy) or a hydroxyl group. More preferably, for example, there may beused a phenyl group which may be substituted and which is represented bythe above formulas (J^(a)) and (J^(b)) wherein:

(1) J¹, J² and J³, whether identical or not, independently representhalogen, an optionally halogenated C₁₋₄ alkyl group or an optionallyhalogenated C₁₋₄ alkoxy group,

(2) J¹ and J², whether identical or not, independently represent ahalogen, an optionally halogenated C₁₋₄ alkyl group or an optionallyhalogenated C₁₋₄ alkoxy group, J³ being hydrogen,

(3) J¹ and J³, whether identical or not, independently represent ahalogen, an optionally halogenated C₁₋₄ alkyl group or an optionallyhalogenated C₁₋₄ alkoxy group, J² being hydrogen,

(4) J¹ and J³ are hydrogen, J² being a halogen,

(5) J⁴ is a di-C₁₋₄ alkylamino group, J⁵ and J⁶ being hydrogen,

(6) J⁴ and J⁶ are hydrogen, J⁵ being a di-C₁₋₄ alkylamino group, or

(7) J⁴ and J⁶, whether identical or not, independently represent anoptionally halogenated C₁₋₄ alkyl group or an optionally halogenatedC₁₋₄ alkoxy group, J⁵ being a C₁₋₃ acyloxy group or a hydroxyl group.

In the above (1) to (7), the optionally halogenated C₁₋₄ alkyl groupincludes methyl, trifluoromethyl, ethyl, etc.; the optionallyhalogenated C₁₋₄ alkoxy group includes methoxy, trifluoromethoxy,ethoxy, etc.; the halogen atom includes fluoro, chloro, etc.; thedi-C₁₋₄ alkylamino group includes N,N-dimethylamino, N,N-diethylamino,etc.; the C₁₋₃ acyloxy group includes formyloxy, acetoxy, etc.

More preferably for Ar, for example, there may be used a penyl groupwhich may be substituted and which is represented by the above formulas(J^(a)) and (J^(b)) wherein:

(a) J¹, J² and J³ are all fluorine, a methyl or methoxy group,

(b) J¹ and J² are both chlorine, a fluorine, isopropyl or methoxy group,J³ being hydrogen,

(c) J¹ and J³ are both chlorine, fluorine, a methyl, ethyl, isopropyl ormethoxy group, J² being hydrogen,

(d) J¹ is an isopropyl group, J² being hydrogen, J³ being a methylgroup,

(e) J¹ and J³ are hydrogen, J² being chlorine,

(f) J¹ and J² are methyl, trifluoromethyl group, J³ is a hydrogen,

(g) J⁴ is an N,N-dimethylamino group, J⁵ and J⁶ being hydrogen,

(h) J⁴ and J⁶ are hydrogen, J⁵ being an N,N-dimethylamino group,

(i) J⁴ and J⁶ are both a methyl, trifluoromethyl or isopropyl group, J⁵being an acetoxy group, or

(j) J⁴ and J⁶ are both a methyl, trifluoromethyl, isopropyl or t-butylgroup, J⁵ being a hydroxyl group.

With respect to the above formulas, two isomers exist with differentrelative configurations of positions 3 and 4 on the condensed ring,provided that ........ is a single bond and Z is ##STR42## (R⁴ has thesame definitions as above), each of which isomers involves two isomerswith different absolute configurations. Provided that ........ is asingle bond and Z is a nitrogen atom, there are two isomers withdifferent absolute configurations of position 3. The present inventionincludes these isomers and mixtures thereof. In this context, theposition 3 of the condensed ring indicates the position of the carbonatom to which the side is bond, the position 4 including the position ofZ.

Preferable examples of the compounds (I) and (I') include compounds ofthe formula: ##STR43## wherein rings A', B' and J independentlyrepresent an optionally substituted benzene ring; either X' or Y'represents --NR^(1a) -- (R^(1a) represents an optionally substitutedhydrocarbon group), --O-- or --S--, the other representing --CO--,--CS-- or --C(R²)R^(2a) -- (R² and R^(2a) independently represent ahydrogen atom or an optionally substituted hydrocarbon group), or eitherX' or Y' represents --N═, the other representing ═CR^(3a) -- (R^(3a)represents a hydrogen atom, an optionally substituted hydrocarbon groupor --OR wherein R represents an optionally substituted hydrocarbongroup; ........ represents a single or double bond; (i) when ........ isa single bond, Z' represents ##STR44## (R^(4a) represents a hydrogenatom or an optionally substituted hydrocarbon group) or a nitrogen atom,or (ii) when ........ is a double bond, Z represents a carbon atom; αrepresents 0, 1 or 2, provided that when --X'--Y'-- is --O--CO--, αrepresents 1 or 2, or a salt thereof.

And, the compound (VI) can be produced by a process which comprisesreacting a compound of the formula: ##STR45## wherein the symbols havethe same definitions as above, or, a salt or reactive derivative thereofwith a compound represented by general formula: ##STR46## wherein thesymbols have the same definitions as above, or a salt thereof. Further,a compound represented by general formula: ##STR47## wherein either X"or Y" represents --NR^(1b) -- (R^(1b) represents a hydrogen atom or anoptionally substituted hydrocarbon group), --O-- or --S--, the otherrepresenting --CO--, --CS-- or --C(R²)R^(2a) -- (R² and R^(2a) have thesame definitions as above), or either X" or Y" represents --N═, theother representing ═CR^(3a) -- (R^(3a) has the same definition asabove), the other symbols having the same definitions as above,unexpectedly exhibits potent ACAT-inhibitory action and is useful as asafe blood cholesterol lowering agent and arteriosclerosis therapeuticcomposition.

Preferable examples of the above symbols include the following:

(1) the substituent of the ring A', B' and J is (i) a halogen, (ii) anoptionally halogenated C₁₋₆ alkyl group, (iii) a C₁₋₆ alkoxy group, (iv)a hydroxyl group, (v) an amino group which may be substituted by C₁₋₄alkyl groups or (vi) a C₁₋₃ acyloxy group,

(2) the ring A' is a benzene ring which may be substituted by one tofour substituents selected from the group consisting of halogen, C₁₋₄alkyl group, C₁₋₄ alkoxy group and halogeno-C₁₋₄ alkyl group,

(3) the ring A' is an optionally substituted benzene ring which isrepresented by the formula: ##STR48## wherein A^(1a), A^(2a) and A^(3a),whether identical or not, independently represent hydrogen, a halogen, aC₁₋₄ alkyl group, a C₁₋₄ alkoxy group or a halogeno-C₁₋₄ alkyl group,

(4) the ring B' is benzene ring which may be substituted by one to foursubstituents selected from the group consisting of halogen, C₁₋₄ alkylgroup and C₁₋₄ alkoxy group,

(5) the ring B' is an optionally substituted benzene ring which isrepresented by the formula: ##STR49## wherein B^(1b), B^(2b) and B^(3b),whether identical or not, independently represent hydrogen, a halogen, aC₁₋₄ alkyl group or a C₁₋₄ alkoxy group,

(6) the ring J is an optionally substituted benzene ring by one to foursubstituents selected from the group consisting of halogen, C₁₋₄ alkylgroup, C₁₋₄ alkoxy group di-C₁₋₄ alkylamino group, C₁₋₃ acyloxy groupand hydroxyl group,

(7) the ring J is an optionally substituted benzene ring which isrepresented by the formula: ##STR50## wherein J^(1a), J^(2a) and J^(3a),whether identical or not, independently represent hydrogen, a halogen, aC₁₋₄ alkyl group, a C₁₋₄ alkoxy group or a di-C₁₋₄ alkylamino group orby the formula: ##STR51## wherein J^(4a), J^(5a) and J^(6a), whetheridentical or not, independently represent hydrogen, a C₁₋₄ alkyl group,a C₁₋₃ acyloxy group or a hydroxyl group,

(8) the --X'--Y'-- is the formula --NR^(1a) --CO--, --NR^(1a)--C(R²)R^(a) --, --N ═CR^(3a) --, --O--CO-- or --CO--O-- (in theseformulas the symbols have the same definitions as above),

(9) α is 1,

In the above in (1) to (9), the halogen includes fluoro, chloro, etc;the optionally halogenated C₁₋₆ alkyl group includes methyl,trifluoromethyl, ethyl, propyl, etc; the C₁₋₆ alkoxy includes methoxy,ethoxy, propoxy, butoxy; the amino group which may be substituted by oneor two C₁₋₄ alkyl groups includes amino, methylamino, dimethylamino,etc; the C₁₋₃ acyloxy includes formyloxy, acetoxy; the C₁₋₄ alkylincludes methyl, ethyl, propyl; the C₁₋₄ alkoxy includes methoxy,ethoxy, propoxy; the halogeno-C₁₋₄ alkyl group includes trifluoromethyl;the di-C₁₋₄ alkylamino includes N,N-dimethylamino.

With respect to the above formulas, rings A', B' and J independentlyrepresent a benzene ring which may have substituents. Such substituentsinclude halogen (e.g., fluorine, chlorine, bromine and iodine,preferably chlorine, fluorine etc.), optionally halogenated alkyl group,optionally halogenated alkoxy group, optionally halogenated alkylthiogroup, C₁₋₇ acylamino group (e.g., formylamino, acetylamino,propionylamino, butyrylamino, benzoylamino), amino group which may besubstituted by one or two C₁₋₄ alkyl groups (e.g., amino, methylamino,ethylamino, propylamino, dimethylamino, methylethylamino,methylpropylamino), C₁₋₃ acyloxy group (e.g., formyloxy, acetoxy,propionyloxy), hydroxyl group, cyano group and carboxyl group.

Examples of the optionally halogenated alkyl group includestraight-chain or branched alkyl groups having 1 to 6 carbon atoms andsuch alkyl groups substituted for by 1 to 5 halogen atoms (e.g.,fluorine, chlorine, bromine and iodine, preferably chlorine, bromineetc.). Specifically, commonly used alkyl groups include methyl,chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl,2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl,3,3,3-trifluoropropyl, isopropyl, 2-trifluoromethylethyl, butyl,4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, 5,5,5-trifluoropentyl, 4-trifluoromethyl-butyl,hexyl, 6,6,6-trifluorohexyl and 5-trifluoromethylpentyl. Preferably usedare straight-chain or branched alkyl groups having 1 to 4 carbon atomssuch as methyl, chloromethyl, difluoromethyl, trichloromethyl,trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, propyl,3,3,3-trifluoropropyl, isopropyl, 2-trifluoromethylethyl, butyl,4,4,4-trifluorobutyl, isobutyl, sec-butyl and tert-butyl, or such alkylgroups substituted for by 1 to 3 of the above-mentioned halogen atoms.

Examples of the optionally halogenated alkoxy group and the optionallyhalogenated alkylthio group include alkoxy groups which may besubstituted for by halogen and alkylthio groups which may be substitutedfor by halogen, resulting from binding of either the above-exemplifiedalkyl group or such alkyl group substituted for by halogen and either anoxygen atom or a sulfur atom, respectively.

Examples of the optionally halogenated alkoxy group includestraight-chain or branched alkoxy groups having 1 to 6 carbon atoms orsuch alkoxy groups substituted for by 1 to 5 of the above-mentionedhalogen atoms. Specifically, commonly used alkoxy groups includemethoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentoxy and hexyloxy.Preferably used are linear or branched alkoxy groups having 1 to 4carbon atoms such as methoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy and sec-butoxy, or such alkoxy groupssubstituted for by 1 to 3 of the above-mentioned halogen atoms.

Examples of the alkylthio group which may be substituted by halogeninclude straight-chain or branched alkylthio groups having 1 to 6 carbonatoms or such alkylthio groups substituted for by 1 to 5 of theabove-mentioned halogen atoms. Specifically, commonly used alkylthiogroups include methylthio, difluoromethylthio, trifluoromethylthio,ethylthio, propylthio, isopropylthio, butylthio,4,4,4-trifluorobutylthio, pentylthio and hexylthio. Preferably used arestraight-chain or branched alkylthio groups having 1 to 4 carbon atomssuch as methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio and 4,4,4-trifluorobutylthio, orsuch alkylthio groups substituted for by 1 to 3 of the above-mentionedhalogen atoms.

Preferable substituents for ring A', B' and J include (i) halogen (e.g.fluorine, chlorine, bromine), (ii) optionally halogenated C₁₋₆ alkylgroup (e.g. methyl, trifluoromethyl, ethyl, propyl), (iii) C₁₋₆ alkoxygroup (e.g. methoxy, ethoxy, propoxy), (iv) hydroxyl group, (v) aminogroup which may be substituted by one or two C₁₋₄ alkyl groups (e.g.methylamino, ethylamino, dimethylamino, diethylamino) and (vi) C₁₋₃acyloxy group (e.g. formyloxy, acetoxy).

The substituent(s) for rings A', B' and J may be located at any positionon the ring. When two or more substituents are present, they may beidentical or not, the number of substituents being 1 to 4, preferably 1to 3, more preferably 1 or 2. Also, the adjacent carbons on ring A', B'or J may bind with a group represented by --(CH₂)l-- (l represents aninteger of from 3 to 5) to form a 5- to 7-membered ring; this case isincluded in the desired above products.

Ring A' is preferably a benzene ring which may be substituted by one tofour substituents selected from the group consisting of halogen (e.g.,chlorine), optionally halogenated C₁₋₄ alkyl group (e.g., methyl, ethyl,isopropyl, trifluoromethyl) and C₁₋₄ alkoxy group (e.g., methoxy),specifically a benzene ring which may be substituted for and which isrepresented by formula A!: ##STR52## wherein A^(1a), A^(2a) and A^(3a),whether identical or not, independently represent hydrogen, a halogen(e.g., fluorine, chlorine), a C₁₋₄ alkyl group (e.g., methyl, ethyl,isopropyl), a C₁₋₄ alkoxy group (e.g., methoxy, ethoxy) or ahalogeno-C₁₋₄ alkyl group (e.g., trifluoromethyl). More preferably, forexample, there may be used benzene rings which may be substituted forand which is represented by the above formula A! wherein:

(1) A^(1a), A^(2a) and A^(3a) are all hydrogen,

(2) A^(1a) and A^(2a) are both hydrogen, A^(3a) being a halogen (e.g.fluorine, chlorine), an optionally halogenated C₁₋₄ alkyl group (e.g.methoxy, ethoxy) or an optionally halogenated C₁₋₄ alkoxy group (e.g.methoxy, trifluoromethoxy, ethoxy),

(3) A^(1a) is hydrogen, A^(2a) and A^(3a), whether identical or not,being independently a halogen (e.g. fluorine, chlorine), a C₁₋₄ alkylgroup (e.g. methyl, ethyl) or a C₁₋₄ alkoxy group (e.g. methoxy,ethoxy), or

(4) A^(2a) is hydrogen, A^(1a) and A^(3a), whether identical or not,being independently a C₁₋₄ alkyl group (e.g. methyl, ethyl).

More preferably for ring A', for example, there may be used optionallysubstituted benzene rings which is represented by the above formula A!wherein:

(a) A^(1a), A^(2a) and A^(3a) are all hydrogen,

(b) A^(1a) and A^(2a) are both hydrogen, A^(3a) being chlorine, amethyl, ethyl, isopropyl, methoxy or trifluoromethyl group,

(c) A^(1a) is hydrogen, A^(2a) and A^(3a) being both a methyl or methoxygroup, or

(d) A^(2a) is hydrogen, A^(1a) and A^(3a) being both a methyl group.

Ring B' is preferably an optionally substituted benzene ring by one tofour substituents selected from the group consisting of halogen (e.g.,fluorine chlorine,), optionally halogenated C₁₋₄ alkyl group (e.g.,methyl, trifluoromethyl, ethyl) and C₁₋₄ alkoxy group (e.g., methoxy,ethoxy), specifically an optionally substituted benzene ring which isrepresented by formula B!: ##STR53## wherein B^(1b), B^(2b) and B^(3b),whether identical or not, independently represent hydrogen, a halogen(e.g., chlorine, fluorine), an optionally halogenated C₁₋₄ alkyl group(e.g., methyl, trifluoromethyl, ethyl) or a C₁₋₄ alkoxy group (e.g.,methoxy, ethoxy). More preferably, for example, there may be usedbenzene rings which may be substituted for and which is represented bythe above formula B! wherein:

(1) B^(1b), B^(2b) and B^(3b) are all hydrogen,

(2) B^(1b) is halogen, an optionally halogenated C₁₋₄ alkyl group (e.g.methyl, trifluoromethyl, ethyl) or an optionally halogenated C₁₋₄ alkoxygroup (e.g. methoxy, trifluoromethoxy, ethoxy), B^(2b) and B^(3b) beingboth hydrogen,

(3) B^(1b) is hydrogen, B^(2b) and B^(3b), whether identical or not,being independently an optionally halogenated C₁₋₄ alkoxy group (e.g.methoxy, trifluoromethoxy, ethoxy), or

(4) B^(1b), B^(2b) and B^(3b), whether identical or not, areindependently an optionally halogenated C₁₋₄ alkoxy group (e.g. methoxy,trifluoromethoxy, ethoxy).

More preferably for ring B', for example, there may be used optionallysubstituted benzene rings which is represented by the above formula B!wherein:

(a) B^(1b), B^(2b) and B^(3b) are all hydrogen,

(b) B^(1b) is chlorine, fluorine, a methyl, trifluoromethyl or methoxygroup, B^(2b) and B^(3b) being both hydrogen,

(c) B^(1b) is hydrogen, B^(2b) and B^(3b) being both a methoxy group, or

(d) B^(1b), B^(2b) and B^(3b) are all a methoxy group.

Ring J may be preferably a benzene ring which may be substituted by oneto four substituents selected from the group consisting of halogen(e.g., chlorine, fluorine, bromine), optionally halogenated C₁₋₄ alkylgroup (e.g., methyl, trifluoromethyl, ethyl, isopropyl, t-butyl), C₁₋₄alkoxy group (e.g., methoxy), di-C₁₋₄ alkylamino group (e.g.,N,N-dimethylamino, N,N-diethylamino), C₁₋₃ acyloxy group (e.g.,formyloxy, acetoxy) and hydroxyl group, specifically an optionallysubstituted benzene ring which is represented by formula J!: ##STR54##wherein J^(1a), J^(2a) and J^(3a), whether identical or not,independently represent hydrogen, a halogen (e.g., chlorine, fluorine),an optionally halogenated C₁₋₄ alkyl group (e.g., methyl,trifluoromethyl, ethyl, isopropyl), a C₁₋₄ alkoxy group (e.g., methoxy)or a di-C₁₋₄ alkylamino group (e.g., N,N-dimethylamino), or by formulaJ'!: ##STR55## wherein J^(4a), J^(5a) and J^(6a), whether identical ornot, independently represent hydrogen, an optionally halogenated C₁₋₄alkyl group (e.g., methyl, trifluoromethyl, isopropyl, t-butyl), a C₁₋₃acyloxy group (e.g., acetoxy) or a hydroxyl group. More preferably, forexample, there may be used a benzene ring which may be substituted andwhich is represented by the above formula J! or J'! wherein:

(1) J^(1a), J^(2a) and J^(3a), whether identical or not, independentlyrepresent halogen, a C₁₋₄ alkyl group or a C₁₋₄ alkoxy group,

(2) J^(1a) and J^(2a), whether identical or not, independently representa halogen, a C₁₋₄ alkyl group or a C₁₋₄ alkoxy group, J^(3a) beinghydrogen,

(3) J^(1a) and J^(3a), whether identical or not, independently representa halogen, a C₁₋₄ alkyl group or a C₁₋₄ alkoxy group, J^(2a) beinghydrogen,

(4) J^(1a) and J^(3a) are hydrogen, J^(2a) being a halogen,

(5) J^(4a) is a di-C₁₋₄ alkylamino group, J^(5a) and J^(6a) beinghydrogen,

(6) J^(4a) and J^(6a) are hydrogen, J^(5a) being a di-C₁₋₄ alkylaminogroup, or

(7) J^(4a) and J^(6a), whether identical or not, independently representa C₁₋₄ alkyl group or a C₁₋₄ alkoxy group, J^(5a) being a C₁₋₃ acyloxygroup or a hydroxyl group.

In the above (1) to (7), the C₁₋₄ alkyl group includes methyl, ethyl,propyl, isopropyl, etc.; the halogen atom includes fluorine, chlorine,bromine, etc.; the C₁₋₄ alkoxy group includes methoxy, ethoxy, propoxy,etc.; the di-C₁₋₄ alkylamino group includes N,N-dimethylamino,N,N-diethylamino, etc.; the C₁₋₃ acyloxy group includes formyloxy,acetoxy, etc.

More preferably for ring J, for example, there may be used optionallysubstituted benzene rings which is represented by the above formula J!or J'! wherein:

(a) J^(1a), J^(2a) and J^(3a) are all fluorine, a methyl or methoxygroup,

(b) J^(1a) and J^(2a) are both chlorine, a fluorine, isopropyl ormethoxy group, J^(3a) being hydrogen,

(c) J^(1a) and J^(3a) are both chlorine, fluorine, a methyl, ethyl,isopropyl or methoxy group, J^(2a) being hydrogen,

(d) J^(1a) is an isopropyl group, J^(2a) being hydrogen, J^(3a) being amethyl group,

(e) J^(1a) and J^(3a) are hydrogen, J^(2a) being chlorine,

(f) J^(4a) is an N,N-dimethylamino group, J^(5a) and J^(6a) beinghydrogen,

(g) J^(4a) and J^(6a) are hydrogen, J^(5a) being an N,N-dimethylaminogroup,

(h) J^(4a) and J^(6a) are both a methyl or isopropyl group, J^(5a) beingan acetoxy group, or

(i) J^(4a) and J^(6a) are both a methyl, isopropyl or t-butyl group,J^(5a) being a hydroxyl group.

With respect to the above formulas, R^(1a) and R independently representan optionally hydrocarbon group; R^(1b), R², R^(2a), R^(3a) and R^(4a)independently represent a hydrogen atom or an optionally substitutedhydrocarbon group. Such hydrocarbon group include alkyl group, alkenylgroup, alkynyl group, cycloalkyl group and aryl group, preferably aalkyl group.

The alkyl group is a straight-chain or branched one having 1 to 6 carbonatoms such as methl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc., preferably astraight-chain or branched alkyl group having 1 to 4 carbon atoms suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl ortert-butyl.

The alkenyl group is one having 2 to 6 carbon atoms such as ethenyl,propenyl, isopropenyl, butenyl, isobutenyl or sec-butenyl, preferably analkenyl group having 2 to 4 carbon atoms such as ethenyl, propenyl orisopropenyl.

The alkynyl group is one having 2 to 6 carbon atoms such as ethynyl,propynyl, isopropynyl, butynyl, isobutynyl or sec-butynyl, preferably analkenyl group having 2 to 4 carbon atoms such as ethynyl, propynyl orisopropynyl.

The cycloalkyl group is a C₃₋₈ cycloalkyl group such as cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl, preferably a C₃₋₆ cycloalkylgroup such as cyclopropyl or cyclobutyl.

The aryl group is one having 6 to 14 carbon atoms such as phenyl,naphthyl, anthryl or phenanthryl, preferably an aryl group having 6 to10 carbon atoms such as phenyl or naphthyl, more preferably phenyl.

Examples of the substituent for the optionally substituted hydrocarbongroup include (i) halogen, (ii) cycloalkyl group, (iii) aryl group, (iv)amino groups which may have an alkyl, alkenyl, cycloalkyl or aryl groupas a substituent, (v) hydroxyl group, (vi) optionally halogenated alkoxygroup, (vii) acyl group, (viii) acyloxy group, (ix) cyano group, (x)optionally protected carboxyl group, (xi) carbamoyl group, (xii)mercapto group, (xiii) alkylthio group, (xiv) sulfo group, and (xv)alkylsulfonyl group.

The optionally substituted hydrocarbon group which may be substitutedfor may be substituted for by 1 to 4, preferably 1 or 2 of theabove-mentioned substituents, whether identical or not.

The halogen atom is exemplified by fluorine, chlorine, bromine andiodine, preferably fluorine and chlorine. The cycloalkyl group isexemplified by C₃₋₆ cycloalkyl groups such as cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. The aryl group is exemplified by C₆₋₁₀ arylgroups such as phonyl and naphthyl. With respect to the amino groupwhich may have an alkyl, alkenyl, cycloalkyl or aryl group as asubstituent, the alkyl group is exemplified by C₁₋₄ alkyl group such asmethyl, ethyl, propyl and isopropyl; the alkenyl group is exemplified byC₂₋₄ alkenyl group such as ethenyl, propenyl, isopropenyl and butenyl;the cycloalkyl group is exemplified by C₃₋₆ cycloalkyl group such ascyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the aryl group isexemplified by C₆₋₁₀ aryl group such as phenyl and naphthyl. Said aminogroup is preferably an amino group which may be substituted by a C₁₋₄alkyl group, such as an amino, methylamino, ethylamino, dimethylamino ordiethylamino group. The optionally halogenated alkoxy group isexemplified by C₁₋₄ alkoxy group such as methoxy, difluoromethoxy,trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy,butoxy, 4,4,4-trifluorobutoxy, isobutoxy and sec-butoxy, or such alkoxygroup substituted for by 1 to 3 halogen atoms (e.g., fluorine,chlorine). The acyl group is a C₁₋₄ acyl group such as formyl, acetyl,propionyl, butyryl or isobutyryl. The acyloxy group is a C₁₋₄ acyloxygroup such as formyloxy, acetyloxy, propionyloxy, butyryloxy orisobutyryloxy. The protecting group for the optionally protectedcarboxyl group is exemplified by C₁₋₄ alkyl groups such as methyl, ethyland t-butyl groups and C₇₋₁₁ -aralkyl group such as benzyl. Thealkylthio group is a C₁₋₄ alkylthio group such as methylthio, ethylthio,propylthio, isopropylthio or butylthio. The alkylsulfonyl group is aC₁₋₄ alkylsulfonyl group such as a methylsulfonyl, ethylsulfonyl,propylsulfonyl, isopropylsulfonyl or butylsulfonyl group.

Example preferable substituents for the hydrocarbon group which may besubstituted for include (i) halogen, (ii) cycloalkyl group, (iii) arylgroup, (iv) amino group which may have an alkyl, alkenyl, cycloalkyl oraryl group as a substituent, (v) hydroxyl group, (vi) optionallyhalogenated alkoxy groups, (vii) acyl group, (viii) acyloxy group, (ix)cyano group, (x) optionally protected carboxyl group and (xi) carbamoylgroup, with greater preference given to (a) C₃₋₆ cycloalkyl group, (b)C₆₋₁₀ aryl group, (c) amino group which may be substituted by C₁₋₄ alkylgroup, and (d) carboxyl group which may be substituted by C₁₋₄ alkylgroup.

The definition of substituents as described in (i) to (x) and (a) to (d)is the same meaning as defined in the above hydrocarbon group.

Examples of preferable groups for R^(1a), R^(1b) and R in --OR include aC₁₋₆ alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,tert-butyl) or C₃₋₆ cycloalkyl group (e.g. cyclopropyl) which may besubstituted by a (i) C₆₋₁₀ aryl (e.g. phenyl), (ii) amino which may besubstituted by one or two C₁₋₄ alkyl groups (e.g. amino, methylamino,dimethylamino), (iii) hydroxyl, (iv) optionally protected carboxyl (e.g.C₁₋₆ alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl,t-butoxycarbonyl) or (v) C₃₋₆ cycloalkyl (e.g. cyclopropyl), preferably,methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl,cyclopropyl, cyclopropylmethyl, benzyl, 2,2-dimethylaminoethyl,2,2-diethylaminoethyl, 2-hydroxyethyl, carboxymethyl,methoxycarbonylmethyl, ethoxycarbonylmethyl and t-butoxycarbonylmethyl.Hydrogen is also preferable for R^(1b).

Preferable groups for R², R^(2a), R^(3a) and R^(4a) include hydrogenatom and C₁₋₄ alkyl group (e.g. methyl, ethyl, propyl, isopropyl, etc.),with greater preference given to hydrogen atoms, methyl, ethyl, propyland isopropyl groups.

With respect to the above formulas, α represents 0, 1 or 2, withpreference given to 1.

In the above formulas, ........ represents a single or double bond; Z'represents ##STR56## (the symbols have the same definitions as above) ora nitrogen atom, provided that ........ is a single bond, or a carbonatom, provided that ........ is a double bond.

In the above formulas, either X' or Y' represents --NR^(1a) -- (thesymbols have the same definitions as above), --O-- or --S--, the otherrepresenting --CO--, --CS-- or --C(R²)R^(2a) -- (the symbols have thesame definitions as above), or either X' or Y' represents --N═, theother representing ═CR^(3a) -- (the symbols have the same definitions asabove). --X'--Y'-- is preferably exemplified by --NR^(1a) -- CO--,--NR^(1a) --CH₂ --, --CO--NR^(1a) --, --O--CO--, --CO--O-- and--N═CR^(3a) -- (the symbols have the same definitions as above), morepreferably --N(CH₃)--CO--, --N(C₂ H₅)-- CO--, --N(CH₃)--CH₂ --, --N(C₂H₅)--CH₂ --, --CO--N(CH₃)--, --CO--N(C₂ H₅)--, --O--CO--, --CO--O--,--N═CH--, --N═C(CH₃)--, --N═C(OCH₃)-- and --N═C(OC₂ H₅)--.

In the above formulas, either X" or Y" represents --NR^(1b) -- (thesymbols have the same definitions as above), --O-- or --S--, the otherrepresenting --CO--, --CS-- or --C(R²)R^(2a) -- (the symbols have thesame definitions as above), or either X" or Y" represents --N═, theother representing ═CR^(3a) -- (the symbols have the same definitions asabove). --X"--Y"-- is preferably exemplified by --NR^(1b) -- CO--,--NR^(1b) --CH₂ --, --CO--NR^(1b) --, --O--CO--, --CO--O-- and--N═CR^(3a) -- (the symbols have the same definitions as above), morepreferably --NHCO--, --N(CH₃)--CO--, --N(C₂ H₅)--CO--, --N(CH₃)--CH₂ --,--N(C₂ H₅)--CH₂ --, --CONH--, --CO--N(CH₃)--, --CO-- N(C₂ H₅)--,--O--CO--, --CO--O--, --N═CH--, --N═C(CH₃)--, --N═C(OCH₃)-- and--N═C(OC₂ H₅)--.

With respect to the above formulas, two isomers exist with differentrelative configurations of positions 3 and 4 on the condensed ring,provided that ........ is a single bond and Z' is ##STR57## (R^(4a) hasthe same definitions as above), each of which isomers involves twoisomers with different absolute configurations. Provided that ........is a single bond and Z' is a nitrogen atom, there are two isomers withdifferent absolute configurations of position 3. The present inventionincludes these isomers and mixtures thereof. In this context, theposition 3 of the condensed ring indicates the position of the carbonatom to which ##STR58## is bound, the position 4 indicating the positionof Z'. Preferable examples of (I) and (I') include also compounds of theformula: ##STR59## wherein rings A" and B" are an optionally substitutedbenzene ring; R^(1c) represents a hydrogen atom, a hydroxyl group, anoptionally substituted hydrocarbon group, an optionally substitutedalkoxy group or an optionally substituted amino group; Q represents anoxygen atom or a sulfur atom;

D¹ represents a C₁₋₃ alkylene group which may be substituted by an oxoor thioxo group;

provided that D¹ is an unsubstituted C₁₋₃ alkylene group, it maycooperate with R^(1C) to form a 5- to 7-membered ring which may besubstituted by an oxo or thioxo group; E² represents --NR^(5a) --(R^(5a) represents a hydrogen atom or an optionally substitutedhydrocarbon group), --O-- or --S--;

R⁵ and R^(1c), taken together, may form a 5- to 7-membered ring whichmay be substituted by an oxo or thioxo group;

G³ represents a bond or a C₁₋₃ alkylene group;

Ar' represents an optionally substituted aryl group or an optionallysubstituted heterocyclic group; provided that, when --D¹ --E² -- is--(CH₂).sub.β --CONH-- (βis 0, 1 or 2), G³ represents a C₁₋₃ alkylenegroup, or a salt thereof.

And, the compound (X) can be produced by a process which comprisesreacting a compound of the formula: ##STR60## wherein L represents aleaving group; D¹ and R^(1c) do not bind together to form a 5- to7-membered ring; the other symbols are the same meaning as definedhereinabove or salt thereof with a compound of the formula:

    H--E.sup.2 --G.sup.3 --Ar'                                 (XII)

wherein all symbols are the same meanings as defined hereinabove or asalt thereof.

Further the compound (X) can be produced by a process which comprisesreacting a compound of the formula: ##STR61## wherein L' represents aleaving group; the other symbols are the same meaning as definedhereinabove or salt thereof, with a compound of the formula:

    L'--G.sup.3 --Ar'                                          (XIV)

wherein all symboles are the same meaning as defined hereinabove or asalt thereof.

Preferable examples of the above symbols include the following:

(1) rings A" and B" are a benzene ring which may be substituted by oneto four substituents selected from the group consisting of halogen (e.g.fluorine, chlorine, bromine), optionally halogenated C₁₋₄ alkyl group(e.g. methyl, trifluoromethyl, ethyl, propyl, isopropyl), hydroxylgroup, optionally halogenated C₁₋₄ alkoxy group (e.g. methoxy,trifluoromethoxy, ethoxy, propoxy, butoxy), optionally halogenated C₁₋₄alkylthio group (e.g. mercapto, methylthio, trifluoromethylthio,ethylthio), amino group, mono- or di-C₁₋₄ alkylamino group (e.g.methylamino, ethylamino, dimethylamino), carboxyl group and C₁₋₄alkoxy-carbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl),

(2) ring A" is represented by the general formula: ##STR62## whereinA^(4a), A^(5a) and A^(6a), whether identical or not, independentlyrepresent a halogen atom (e.g. fluorine, chlorine, bromine), anoptionally halogenated C₁₋₄ alkyl group (e.g. methyl, trifluoromethyl,ethyl, propyl, isopropyl) or an optionally halogenated C₁₋₄ alkoxy group(e.g. methoxy, trifluoromethoxy, ethoxy, propoxy, butoxy),

(3) ring B" is represented by the general formula: ##STR63## whereinB^(4b), B^(5b) and B^(6b), whether identical or not, independentlyrepresent a halogen atom, an optionally halogenated C₁₋₄ alkyl group(e.g. methyl, trifluoromethyl, ethyl, propyl, isopropyl) or anoptionally halogenated C₁₋₄ alkoxy group (e.g. methoxy,trifluoromethoxy, ethoxy, propoxy, butoxy),

(4) R^(1c) is a hydrogen atom or a C₁₋₄ alkyl group (e.g. methyl, ethyl,propyl) which may be substituted by one or two substituents selectedfrom the group consisting of hydroxyl group, C₁₋₄ alkoxy group (e.g.methoxy, ethoxy), amino group, mono- or di-C₁₋₄ alkylamino group (e.g.methylamino, ethylamino, dimethylamino, diethylamino), C₁₋₄alkoxy-carbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl), carboxylgroup, carbamoyl group and phenyl group,

(5) R^(1c) is a hydrogen atom or a C₁₋₄ alkyl group (e.g. methyl, ethyl,propyl),

(6) R^(5a) is a hydrogen atom or a C₁₋₄ alkyl group (e.g. methyl, ethyl,propyl) which may be substituted for by one or two substituents selectedfrom the group consisting of hydroxyl group, C₁₋₄ alkoxy group (e.g.methoxy, ethoxy, propoxy), amino group, mono- or di-C₁₋₄ alkylaminogroup (e.g. methylamino, ethylamino, dimethylamino, diethylamino), C₁₋₄alkoxy-carbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl), carboxylgroup, carbamoyl group and phenyl group,

(7) R^(5a) is a hydrogen atom or a C₁₋₄ alkyl group (e.g. methyl, ethyl,propyl),

(8) the optionally substituted aryl group represented by Ar', is a C₆₋₁₀group (e.g. phenyl, naphthyl) which may have one to three substituentsselected from the group consisting of an optionally halogenated C₁₋₄alkyl group (e.g. methyl, trifluoromethyl, ethyl, propyl, isopropyl),halogen atom (e.g. fluorine, chlorine, bromine), nitro group, hydroxylgroup, optionally halogenated C₁₋₄ alkoxy group (e.g. methoxy,trifluoromethoxy, ethoxy, butoxy), amino group, mono- or di-C₁₋₄alkylamino group (e.g. methylamino, ethylamino, dimethylamino,diethylamino), C₁₋₄ alkoxy-carbonyl group (e.g. methoxycarbonyl,ethoxycarbonyl), carboxyl group and carbamoyl group,

(9) the optionally substituted aryl group represented by Ar', is aphenyl group which may have one to three substituents selected from thegroup consisting of an optionally halogenated C₁₋₄ alkyl group (e.g.methyl, trifluoromethyl, ethyl, propyl, isopropyl), halogen atom (e.g.fluorine, chlorine, bromine) and C₁₋₄ alkoxy group (e.g. methoxy,ethoxy, propoxy),

(10) the optionally substituted heterocyclic group represented by Ar',is furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl,pyrazolyl, pyridyl, pyridazinyl, quinolyl, isoquinolyl, thiazolyl,thiadiazolyl or thiophenyl which may have one to three substituentsselected from the group consisting of halogen atom (e.g. fluorine,chlorine, bromine), optionally halogenated, C₁₋₄ alkyl group (e.g.methyl, trifluoromethyl, ethyl, propyl, isopropyl), C₃₋₆ cycloalkylgroup (e.g. cyclopropyl), hydroxyl group, C₁₋₄ alkoxy group (e.g.methoxy, ethoxy, propoxy), C₁₋₄ alkylthio group (e.g. methylthio,ethylthio, propylthio), amino group, mono- or di-C₁₋₄ alkylamino group(e.g. methylamino, ethylamino, dimethylamino, diethylamino), C₁₋₄alkoxy-carbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl) andcarboxyl group,

(11) the heterocyclic group represented by Ar', is furyl, thienyl orpyridyl which may have one to three substituents selected from the groupconsisting of halogen atom (e.g. fluorine, chlorine, bromine), C₁₋₄alkyl group (e.g. methyl, ethyl, propyl) and C₁₋₄ alkoxy group (e.g.methoxy, ethoxy, propoxy),

(12) Q is an oxygen atom.

(13) D¹ is --CO--, --CS--, --CH₂ --, --CH₂ CH₂ --, --CH₂ CO-- or --CH₂CH₂ CO--,

(14) D¹ is --CO-- or --CH₂ CO--,

(15) D¹ is --CH₂ -- or --CH₂ CH₂ --,

(16) D¹ is --CO-- or --CH₂ --,

(17) E² is --NR^(5c) -- (R^(5c) is a hydrogen atom or a C₁₋₄ alkyl group(e.g. methyl, ethyl, propyl)),

(18) E² is --O--,

(19) G³ is --CH₂ -- or --CH₂ CH₂ --,

(20) ring A" is a benzene ring which may be substituted by two C₁₋₄alkyl group (e.g. methyl, ethyl, propyl); ring B is a benzene ring whichmay be substituted by a C₁₋₄ alkyl group (e.g. methyl, ethyl, propyl);R^(1c) is a C₁₋₄ alkyl group (e.g. methyl, ethyl, propyl), R^(5a) is ahydrogen atom or a C₁₋₄ alkyl group (e.g. methyl, ethyl, propyl), D¹ is--CO--; E² is --NR^(5c) -- (R^(5c) represents a hydrogen atom or a C₁₋₄alkyl group (e.g. methyl, ethyl, propyl)), G³ is --CH₂ --; Ar' is aphenyl group substituted by one to three optionally halogenated C₁₋₄alkyl groups (e.g. methyl, trifluoromethyl, ethyl),

(21)N--(3,5-bistrifluoromethyl)benzyl-1,2-dihydro-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamide,N-(3,5-bistrifluoromethyl)benzyl-1,2-dihydro-N,2-dimethyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamideor N- 3,5-bis(trifluoromethyl)benzyl!-1,2-dihydro-N,2,6,7-tetramethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide,

The terms of ring A" and B" are the same meaning as defined above in thering A and B of (I) and (I').

Preferable substituents on ring A" and B" include halogen (e.g. fluoro,chloro, bromo, etc.), optionally halogenated C₁₋₄ alkyl (e.g. methyl,chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl,2-bromoethyl, 2,2,2-trifluoroethyl, propyl, 3,3,3-trifluropropyl,isopropyl, 2-trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl,isobutyl, sec-butyl, tert-butyl, etc.), optionally halogenated C₁₋₄alkoxy (e.g. methoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, etc.), optionallysubstituted C₁₋₄ alkylthio (e.g. methylthio, difluoromethylthio,trifluoromethylthio, ethylthio, propylthio, isopropylthio, buthylthio,4,4,4-trifluorobuthylthio, etc.), hydroxyl, amino, mono-or di-C₁₋₄alkylamino (e.g. methylamino, ethylamino, propylamino, dimethylamino,diethylamino, etc.), carboxyl and C₁₋₄ alkoxy-carbonyl (e.g.methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.).

More preferable substituents on ring A" and B" include halogen (e.g.fluoro, chloro, bromo, etc.), optionally halogenated C₁₋₄ alkyl (e.g.methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,ethyl, 2-bromoethyl, 2,2,2,-trifluoroethyl, propyl, 3,3,3-trifluoropropyisopropyl, 2-trifluoromethylethyl, buthyl, 4,4,4-trifluorobutyl,isobutyl, sec-butyl, tert-butyl, etc.), optionally halogenated C₁₋₄alkoxy (e.g. methoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, etc.), hydroxyl, amino andmono- or di- C₁₋₄ alkylamino (e.g. methylamino, ethylamino, propylamino,dimethylamino, diethylamino, etc.).

Specifically more preferable substituents on ring A" and B" includehalogen (e.g. fluoro, chloro, bromo, etc.), optionally halogenated C₁₋₄alkyl (e.g. methyl, chloromethyl, difluoromethyl, trichloromethyl,trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, propyl,3,3,3-trifluoropropy isopropyl, 2-trifluoromethylethyl, buthyl,4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, etc.), optionallyhalogenated C₁₋₄ alkoxy (e.g. methoxy, difluoromethoxy,trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy,butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, etc.).

The substituent(s) for rings A" and B" may be located at any position onthe ring. When two or more substituents are present, they may beidentical or not, the number of substituents being 1 to 4, preferably 1to 3, more preferably 1 or 2. Also, the adjacent carbons on ring A" orB" may bind with a group represented by --(CH₂)l-- (l represents aninteger of from 3 to 5) to form a 5- to 7-membered ring.

Referring to ring A", concrete examples of the moiety ##STR64## includegroups of the formula: ##STR65## where A^(4a), A^(5a) and A^(6a) are thesame or different and each means a halogen atom such as chloro, fluoro,etc., an optionally halogenated C₁₋₄ alkyl group such as methyl, ethyl,isopropyl trifluoromethyl, etc., or an optionally halogenated C₁₋₄alkoxy group such as methoxy, trifluoromethoxy, ethoxy, etc.

In A^(4a), A^(5a) and A^(6a), preferably a C₁₋₄ alkyl group (e.g.methyl, ethyl, etc.).

Referring to ring B", concrete examples of the moiety ##STR66## includegroups of the formula: ##STR67## where B^(4b), B^(5b), B^(6b), B^(7b),B^(8b) and B^(9b) are the same or different and each means a halogenatom such as chloro, fluoro, etc., an optionally halogenated C₁₋₄ alkylgroup such as methyl, trifluoromethyl, ethyl, etc., or an optionallyhalogenated C₁₋₄ alkoxy group such as methoxy trifluoromethoxy, ethoxy,etc.

Preferred examples of the ring B" are groups of the formula: ##STR68##wherein B^(4b), B^(5b) and B^(6b) is the same meaning hereinbefore.

In B^(4b), B^(5b) and B^(6b), preferably a C₁₋₄ alkyl group (e.g.methyl, ethyl, etc.) and a C₁₋₄ alkoxy group (e.g. methoxy, ethoxy,etc.).

With respect to the above formula, R^(1c) represents a hydrogen atom,hydroxyl group, optionally substituted hydrocarbon group, optionallysubstituted alkoxy group or optionally substituted amino group. The"hydrocarbon group" of "optionally substituted hydrocarbon group"represented by R^(1c) is used, for example, C₁₋₆ alkyl group, C₃₋₆cycloalkyl group or C₃₋₆ cycloalkyl-C₁₋₄ alkyl group and so on. The C₁₋₆alkyl group includes, for example, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, etc.,preferably a C₁₋₄ alkyl group such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, etc. The C₃₋₆ cycloalkyl groupincludes, for example, cyclopropyl, cyclopentyl or cyclohexyl, etc. TheC₃₋₆ cycloalkyl-C₁₋₄ alkyl group includes, for example,cyclopropylmethyl, cyclopropylethyl, etc.

The preferable substituent of the hydrocarbon group hereinabove iscommonly used a C₁₋₄ alkyl group such as methyl, ethyl, propyl,isopropyl, butyl and so on.

The substituent of the hydrocarbon group is used one to five, preferablyone to three, more preferable one or two substituent(s) selected fromthe group consisting of halogen atom (e.g. fluoro, chloro, bromo, etc.),nitro, cyano, hydroxyl, C₁₋₄ alkoxy group (e.g. methoxy, ethoxy,propoxy, butoxy, isopropoxy, etc.), C₁₋₄ alkylthio group (e.g.methylthio, ethylthio, propylthio, etc.), amino, mono- or di- C₁₋₄alkylamino group (e.g. methylamino, ethylamino, propylamino,dimethylamino, diethylamino, etc.), cyclic amino group (e.g., 5- to9-membered cyclic amino which may contain 1 to 3 hetero-atoms such asoxygen and sulfur in addition to nitrogen as ring-constituent members,such as pyrrolidino, piperidino, morpholino, etc.), C₁₋₄alkyl-carbonylamino group (e.g. acetylamino, propionylamino,butyrylamino, etc.), C₁₋₄ alkylsulfonylamino group (e.g.methylsulfonylamino, ethylsulfonylamino, etc.), C₁₋₄ alkoxy-carbonylgroup (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.),carboxyl, C₁₋₆ alkyl-carbonyl group (e.g. methylcarbonyl, ethylcarbonyl,propylcarbonyl, etc.), carbamoyl, ethylcarbamoyl, etc.), mono- ordi-C₁₋₄ alkylcarbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl, etc.),C₁₋₆ alkylsulfonyl group (e.g. methylsulfonyl, ethylsulfonyl,propylsulfonyl, etc.), and pheny group which may be substituted by C₁₋₃alkoxy group (e.g. methoxyphenyl, ethoxyphenyl, etc.).

As the halogen atoms, among the above-mentioned substituents, fluoro,chloro, bromo and iodo may be reckoned and chloro or fluoro ispreferred.

Preferable examples of substituent of hydrocarbon group include hydroxylgroup, C₁₋₄ alkoxy group (e.g. methoxy, ethoxy, propoxy, etc.), aminogroup, mono- or di- C₁₋₄ alkylamino group (e.g. methylamino, ethylamino,dimethylamino, diethylamino, etc.), C₁₋₄ alkoxy-carbonyl group (e.g.methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), carboxyl group,carbamoyl group, phenyl group, more preferably carboxyl group andcarbamoyl group.

Preferable examples of R^(1c) include a hydrogen atom and a C₁₋₄ alkylgroup (e.g. methyl, ethyl, n-propyl, n-butyl, etc.), more preferably aC₁₋₄ alkyl group (e.g. methyl, ethyl, n-propyl, etc.),

The "alkoxy group" of the "optionally substituted alkoxy group"represented by R^(1c) is, for example, C₁₋₄ alkoxy group (e.g. methoxy,ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, etc.) and so on. Thesubstituent of the "alkoxy group" is the same meaning as defined in thesubstituent of "hydrocarbon group".

The substituent of the "optionally substituted amino group" representedby R^(1c) includes (i) C₁₋₄ alkyl group (e.g. methyl, ethyl, propyl,isopropyl, etc.), (ii) C₁₋₄ alkyl-carbonyl group (e.g. acetyl,propyonyl, butyril, etc.), (iii) C₁₋₄ alkoxy-carbonyl (e.g.methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), (iv) halogenatom (e.g. fluoro, chloro, etc.) and (v) phenyl group which may besubstituted by a C₁₋₄ alkyl (e.g. methyl, ethyl, etc.), a C₁₋₄ alkoxygroup (e.g. methoxy, ethoxy, etc.) or a halogen atom (e.g. fluoro,chloro, etc.) such as phenyl, 4-chlorophenyl, 3-chlorophenyl,2-chlorophenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl,3-methoxyphenyl, 2-methoxyphenyl, etc. The optionally substituted aminogroup may be substituted by one or two substituent(s).

With respect to the above formula, Q represents an oxygen atom and asulfur atom, preferably an oxygen atom.

With respect to the above formula, D¹ represents a C₁₋₃ alkylene groupwhich may be substituted by an oxo or thioxo group.

The C₁₋₃ alkylene group includes, for example, --CH₂ --, --CH₂ CH₂ --,--CH₂ CH₂ CH₂ -- and --CH(CH₃)--CH₂ -- and so on.

Preferable examples of D¹ include --CO--, --CS--, --CH₂ --, --CH₂ CH₂--, --CH₂ CO--, --CH₂ CS--, --CH₂ CH₂ CO-- and --CH₂ CH₂ CS--, morepreferably --CO--, --CH₂ --, --CH₂ CH₂ -- and --CH₂ CO--, specially--CO-- and --CH₂ -- are more preferable.

Provided that D¹ is an unsubstituted C₁₋₃ alkylene group, its carbonatoms may cooperate with R^(1c) to form a 5- to 7-membered ring whichmay be substituted by an oxo or thioxo group. Specifically, the compound(X) is represented by the formula: ##STR69## wherein ring K' is a 5- to7-membered ring which may be substituted by an oxo or thioxo group; hrepresents an integer from 3 to 5; the other symbols have the somedefinitions as above, or a salt thereof, preferably represented by theformula: ##STR70## wherein the symbols have the same definitions asabove or below.

With respect to the above formulas, E² represents --NR^(5a) -- (R^(5a)represents a hydrogen atom or an optionally substituted hydrocarbongroup), --O-- or --S--. The hydrocarbon group represented by R^(5a) ispreferably a C₁₋₆ alkyl group, a C₃₋₆ cycloalkyl group, a C₃₋₆cycloalkyl-C₁₋₄ alkyl group or the like, more preferably a C₁₋₄ alkylgroup (e.g. methyl, ethyl, propyl). The C₁₋₄₆ alkyl group is exemplifiedby methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, neopentyl and hexyl, with preference given to C₁₋₄alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl and tert-butyl. The C₃₋₆ cycloalkyl group is exemplified bycyclopropyl, cyclopentyl and cyclohexyl. The C₃₋₆ cycloalkyl-C₁₋₄ alkylgroup is exemplified by cyclopropylmethyl and cyclopropylethyl. R^(5a)is preferably a hydrogen atom or a C₁₋₄ alkyl group (e.g., methyl,ethyl, propyl, isopropyl, butyl), with greater preference given to C₁₋₄alkyl groups (e.g., methyl, ethyl, propyl, isopropyl). The substituentthe alkyl group may have is exemplified by the same groups as the"substituents" for the "optionally halogenated hydrocarbon group"represented by R^(1c). Preferable substituents for the hydrocarbon grouprepresented by R^(5a) are the same as specified for substituents for thehydrocarbon group represented by R^(1c) ; C₁₋₃ alkoxy group (e.g.,methoxy, ethoxy), mono- or di-C₁₋₂ alkylamino group (e.g.,dimetylamino), carbamoyl group, carboxyl group etc. are used commonly.The number of substituents is preferably 1 or 2. Preferable examples orE² are --NH-- or --O--.

Also, R^(5a) and R^(1c) may bind together to form a 5- to 7-memberedring which may be substituted by an oxo or thioxo group. Specifically,the compound (X) is represented by the general formula: ##STR71##wherein ring K" is a 5- to 7-membered ring which may be substituted byan oxo or thioxo group; i represents an integer from 1 to 3, the totalcarbon number of D¹ and --(CH₂)_(i) -- being 3 to 5; the other symbolshave the same definitions as above or below. Preferably, it isrepresented by the formula: ##STR72## wherein D^(a) and M independentlyrepresent --CH₂ -- or --CO--; the other symbols have the samedefinitions as above or below.

In the above formulas, Ar' represents an aryl group which may have anoptionally substituted substituent or an optionally substitutedheterocyclic group. The optionally substituted aryl group is the samemeaning as defined in Ar.

Preferable examples of substituent of the aryl group represented by Ar'include optionally halogenated C₁₋₄ alkyl group (e.g., methyl,chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl,2-bromoethyl, 2,2,2-trifluoroethyl, propyl, isopropyl,3,3,3-trifluoropropyl), halogen atom (e.g., fluorine, chlorine,bromine), nitro group, hydroxyl group, optionally halogenated C₁₋₄alkoxy group (e.g., methoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy), amino group, mono- or di-C₁₋₄ alkylamino group(e.g., methylamino, ethylamino, dimethylamino, diethylamino), C₁₋₄alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl), carboxylgroup and carbamoyl group, more preferably, optionally halogenated C₁₋₄alkyl group (e.g., methyl, chloromethyl, difluoromethyl,trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl), halogen atom(e.g., fluorine, chlorine, bromine) and C₁₋₄ alkoxy group (e.g.,methoxy, ethoxy, propoxy).

The heterocyclic group represented by Ar', is exemplified by 5- to9-membered, preferably 5- or 6-membered aromatic heterocyclic groupswhich may have one to four, preferably one or two hetero atoms such asnitrogen, oxygen and sulfur atoms in addition to carbon atoms.

Such aromatic heterocyclic group is the same meaning as defined in Ar.

Preferable example of the heterocyclic group represented by Ar' include5- or 6-membered heterocyclic groups such as furyl, thienyl, pyrrolyl,oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl,quinolyl, isoquinolyl, thiazolyl, thiadiazolyl and thiophenyl, withgreater preference given to furyl, thienyl, pyridyl etc.

The substituent in the "optionally substituted heterocyclic group,"represented by Ar', is the same meaning as defined in Ar.

Preferable examples of substituent of the heterocyclic ring representedby Ar' include halogen atom (e.g., fluorine, chlorine, bromine),optionally halogenated C₁₋₄ alkyl group (e.g., methyl, chloromethyl,difluoromethyl, trifluoromethyl, ethyl), C₃₋₆ cycloalkyl group (e.g.,cyclopropyl, cyclobutyl), hydroxyl groups, optionally halogenated C₁₋₄alkoxy group (e.g., methoxy, difluoromethoxy, trifluoromethoxy, ethoxy),optionally halogenated C₁₋₄ alkylthio group which may be halogenated(e.g., methylthio, ethylthio), amino group, mono- or di-C₁₋₄ alkylaminogroup (e.g., methylamino, ethylamino, dimethylamino, diethylamino), C₁₋₄alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl) andcarboxyl group, with greater preference given to halogen atom (e.g.,fluorine, chlorine), C₁₋₄ alkyl group (e.g., methyl, ethyl), C₃₋₆cycloalkyl group (e.g., cyclopropyl, cyclobutyl), hydroxyl group, C₁₋₄alkoxy group (e.g., methoxy, ethoxy) and carboxyl groups etc.

Ar' is preferably a phenyl group which may have one to threesubstituents selected from the group consisting of halogen atom (e.g.,fluorine, chlorine), optionally halogenated C₁₋₄ alkyl group (e.g.,methyl, difluoromethyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl,propyl, isopropyl) and optionally halogenated C₁₋₄ alkoxy group (e.g.,methoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy). Also preferred are 5- or6-membered heterocyclic group (e.g., furyl, pyridyl, thienyl, thiazolyl,thiadiazolyl) which have one to three hetero atom (e.g., nitrogen atoms,oxygen atoms, sulfur atoms) in addition to carbon atoms and which may besubstituted by an optionally halogenated C₁₋₄ alkyl group (e.g., methyl,trifluoromethyl, ethyl), a C₁₋₄ alkoxy group (e.g., methoxy, ethoxy,propoxy) or a C₃₋₆ cycloalkyl group (e.g., cyclopropyl).

G³ represents a bond or a C₁₋₃ alkylene group. The C₁₋₃ alkylene groupinclude --CH₂ --, --CH₂ CH₂ --, --CH₂ CH₂ CH₂ -- and --CH(CH₃)CH₂ --. G³is preferably --CH₂ -- or --CH₂ CH₂ --, --CH₂ -- being commonly used.

In the above formula, L represents a leaving group. This group isexemplified by hydroxyl group, halogen atom (e.g., chlorine, bromine,iodine), substituted sulfonyloxy group (e.g., methanesulfonyloxy andp-toluenesulfonyloxy groups), acyloxy group (e.g., acetoxy andbenzoyloxy groups), and oxy group substituted by a heterocyclic group oran aryl group (e.g., succinimide, benzotriazole, quinoline or4-nitrophenyl group).

In the above formula, L' and L" represents a leaving group. This leavinggroup is exemplified by halogen atom and substituted sulfonyloxy groupamong the leaving groups exemplified for L above.

When compound (I) and (I') of the present invention has a basic groupsuch as an amino group or a substituted amino group, it may form aphysiologically acceptable acid addition salt. Such salts include thosewith inorganic acids (e.g., hydrochloric acid, phosphoric acid,hydrobromic acid, sulfuric acid) and those with organic acids (e.g.,acetic acid, formic acid, propionic acid, fumaric acid, maleic acid,succinic acid, tartaric acid, citric acid, malic acid, oxalic acid,benzoic acid, methanesulfonic acid, benzenesulfonic acid). When compound(I) and (I') of the present invention has an acidic group such as--COOH, it may form a salt with an inorganic base (e.g., alkali metalsor alkaline earth metals such as sodium, potassium and magnesium,ammonia) or an organic base (e.g., tri-C₁₋₃ alkylamine such astriethylamine).

Production methods for compound (I) and (I') or a salt thereof of thepresent invention are described below.

Compound (I) and (I') or a salt thereof of the present invention can,for example, be produced by the following methods 1 and 2. Specifically,compound (I) and (I') or a salt thereof is produced by 1 reacting aheterocyclic compound or a salt thereof having a leaving group L,represented by general formula (II) and a compound or a salt thereofrepresented by formula (III), or by 2 reacting a heterocyclic compoundor a salt thereof represented by general formula (IV) and a compound ora salt thereof represented by formula (V).

Methods 1 and 2 are hereinafter described in detail.

Method 1

This method generally affords two options: i) acylation, conducted whenthe L-linked methylene group in D is substituted by an oxo or thioxogroup, and ii) alkylation, conducted when the L-linked methylene groupin D is unsubstituted.

i) Acylation: When the leaving group L of compound (II) is a hydroxylgroup, it is preferable to use an appropriate condensing agent or toconvert the leaving hydroxyl group to another leaving group asappropriate (e.g., an acyloxy group as described above, or an oxy groupsubstituted by a heterocyclic group or aryl group) and then react itwith compound (III) or a salt thereof. Such condensing agents includedicyclohexylcarbodiimide (DCC), diethyl cyanophosphate (DEPC) anddiphenylphosphorylazide (DPPA). When these condensing agents are used,the reaction is preferably carried out in a solvent (e.g., ethers,esters, hydrocarbons, amides, sulfoxides) such as tetrahydrofuran,dioxane, dimethoxyethane, ethyl acetate, benzene, toluene,N,N-dimethylformamide and dimethylsulfoxide. This reaction may beaccelerated in the presence of a base, and is carried out at about -10°to 100° C., preferably about 0° to 60° C. Reaction time is normally 5minutes to 96 hours, preferably 0.5 to 72 hours. The mount of compound(III) or a salt thereof or condensing agent used is 1 to 5 molequivalents, preferably 1 to 3 mol equivalents per mol of compound (II)or a salt thereof. Examples of bases which can be used includealkylamines such as triethylamine and cyclic amines such asN-methylmorpholine and pyridine, their amount being 1 to 5 molequivalents, preferably 1 to 3 mol equivalents per mol of compound (II)or a salt thereof.

Compound (II) as a reactive derivative is preferably an acid halide(e.g., chloride, bromide), acid anhydride, mixed acid anhydride (e.g.,anhydride with methylcarbonic acid, anhydride with ethylcarbonic acid,anhydride with isobutylcarbonic acid), active ester (e.g., ester withhydroxysuccinimide, ester with 1-hydroxybenzotriazole, ester withN-hydroxy-5-norbornane-2,3-dicarboxymide, ester with p-nitrophenol,ester with 8-oxyquinoline), with preference given to acid halides. Thereaction of compound (III) or a salt thereof and compound (II) isnormally carried out in a solvent (e.g., halogenated hydrocarbonsethers, esters, hydrocarbons, amides such as chloroform,dichloromethane, ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane,ethyl acetate, benzene, toluene, pyridine, and N,N-dimethylformamide).This reaction may be accelerated in the presence of a base. Reactiontemperature is normally about -10° to 120° C., preferably about 0° to100° C. Reaction time is normally 5 minutes to 48 hours, preferably 0.5to 24 hours. The mounts of compound (III) used is 1 to 5 molequivalents, preferably 1 to 3 mol equivalents per mol of compound (II)or a salt thereof. Examples of bases which can be used includealkylamines such as triethylamine, cyclic mines such asN-methyl-morpholine and pyridine, aromatic amines such asN,N-dimethylaniline and N,N-diethylaniline, alkali metal carbonates suchas sodium carbonate and potassium carbonate and alkali metal hydrogencarbonates such as sodium hydrogen carbonate and potassium hydrogencarbonate, their amount being 1 to 5 mol equivalents, preferably 1 to 3mol equivalents per mol of compound (III) or a salt thereof. Also, whena water-immiscible solvent is used for the reaction, the reaction systemmay consist of two phases including water.

ii) Alkylation: In the reaction with compound (III), the leaving group Lof compound (II) is preferably one of the above-mentioned halogen atomsor substituted sulfonyloxy groups.

Although compound (III) may be used as such in a free form, it may beconverted to a salt such as with an alkali metal such as lithium, sodiumor potassium before being used in the reaction. The amount of compound(III) or a salt thereof reacted is 1 to 10 mol equivalents, preferably 1to 5 mol equivalents per mol of compound (II). This reaction is normallycarried out in a solvent. Preferable solvents include halogenatedhydrocarbons such as dichloromethane and chloroform, nitriles such asacetonitrile, ethers such as dimethoxyethane and tetrahydrofuran, anddimethylformamide, dimethylsulfoxide and hexamethylphosphoramide.Addition of a base promotes the reaction. Bases preferred for thispurpose include sodium hydrogen carbonate, potassium hydrogen carbonate,sodium carbonate, potassium carbonate, sodium hydride, potassiumhydride, sodium amide, sodium methoxide, triethylamine,diisopropylethylamine and pyridine. Also, in this reaction, compound(III) may be converted to one of the above-mentioned alkali metal salts,alkaline earth metal salts etc. and then reacted with compound (II), inplace of using a base. When E of compound (II) is --NR⁵ --, compound(III) itself may be used as a base, in place of using one of the abovebases. Varying depending on types of compounds (II) and (III) andsolvent and other reaction conditions, the mount of base used isnormally 1 to 10 mol equivalents, preferably 1 to 5 mol equivalents permol of compound (III). Reaction temperature is about -50° to 200° C.,preferably -20° to 150° C. Varying depending on type of compound (III)or a salt thereof, reaction temperature and other factors, reaction timeis 1 to 72 hours, preferably 1 to 24 hours.

Method 2

This method is carried out in the same manner as the alkylationdescribed in term ii), method 1. Specifically, the same procedures asthose of the method described in term ii) is followed, using compound(V) in place of compound (II) and using compound (IV) or a salt thereofin place of compound (III) or a salt thereof.

Of the compounds represented by formula (I), a compound or a saltthereof represented by the general formula (I^(a)): ##STR73## whereineither of X^(a) and Y^(a) is --NR^(1a) -- (R^(1a) had the samedefinition as above) or --O--, the other representing --CO--; the othersymbols have the same definitions as above, can be produced bysubjecting to reduction a compound or a salt thereof represented byformula (I^(b)): ##STR74## wherein the symbols have the same definitionsas above.

This reaction, wherein an amide compound represented by general formula(I^(b)) is reduced to convert its double bond to a single bond, iscarried out by various methods. For example, it is preferable to use amethod wherein the starting material is reduced in the presence of ametal catalyst for catalytic reduction. Examples of the catalysts forthis catalytic reduction method include platinum catalysts such asplatinum black, platinum oxide and platinum carbon, palladium catalystssuch as palladium black, palladium oxide, palladium barium sulfate andpalladium carbon, and nickel catalysts such as reduced nickel, oxidizednickel, Raney nickel and Urushibara nickel. This reaction is normallycarried out in a solvent. An organic acid such as formic acid, aceticacid or propionic acid is used as the solvent, or an alcohol such asmethanol, ethanol, propanol or isopropanol, an ether such astetrahydrofuran or dioxane, or an ester such as ethyl acetate, is usedas the solvent in the presence of the above organic acid or an inorganicacid such as phosphoric acid, sulfuric acid or hydrochloric acid.Reaction temperature is normally 0° to 200° C., preferably 20° to 110°C. Reaction time is normally 0.5 to 48 hours, preferably 1 to 16 hours.Although the reaction is normally carried out under normal pressure, itmay be carried out under increased pressure (3 to 10 atm) as necessary.Varying depending on catalyst type, the amount of catalyst used isnormally 0.1 to 10% (w/w), relative to compound (I^(b)).

Of the compounds represented by formula (I), a compound represented bythe general formula (I^(c)): ##STR75## wherein the symbols have the samedefinitions as above or a salt thereof can be produced by reacting acompound represented by general formula (I^(d)): ##STR76## wherein thesymbols have the same definitions as above, or a salt thereof with analkylating agent represented by the formula R¹ -L (R¹ has the samedefinition as above; L represents a leaving group) to produce a compoundrepresented by general formula (I^(e)): ##STR77## wherein the symbolshave the same definitions as above or a salt thereof, which is thensubjecting to a reducing reaction.

This reaction, wherein a quinolineamide compound represented by generalformula (I^(d)) is reacted with an alkylating agent represented by R¹ -Lto a quaternary salt (I^(e)), which is then reduced to produce acompound represented by general formula (I^(c)). Examples of thealkylating agent R¹ -L used to convert formula (I^(d)) to (I^(e))include alkane halides (e.g., chloride, bromide, iodide), sulfates andsulfonates (e.g., methanesulfonate, p-toluenesulfonate,benzenesulfonate), with preference given to alkyl halides. The amount ofalkylating agent used is 1 to 100 mol equivalents, preferably 1 to 30mol equivalents per mol of compound (I^(d)). This reaction is normallycarried out in a solvent. Examples of the solvent include alcohols suchas methanol, ethanol, propanol and isopropanol, ethers such astetrahydrofuran and dioxane, esters such as ethyl acetate, andhalogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane.The alkylating agent itself may be used as the solvent. Reactiontemperature is normally 10° to 200° C., preferably 20° to 110° C.Reaction time is normally 0.5 to 24 hours, preferably 1 to 16 hours.

The thus-obtained quaternary salt (I^(e)) is normally reduced to (I^(c))in an inert solvent in the presence of a metal hydride. Examples ofmetal hydrides which can be used for this purpose include sodiumborohydride, lithium borohydride, zinc borohydride, sodiumcyanoborohydride and lithium cyanoborohydride, with preference given tosodium borohydride. Reaction solvents which can be used include loweralcohols such as methanol and ethanol, ethers such as dioxane andtetrahydrofuran and hydrocarbons such as benzene and toluene. Thesesolvents may be used singly or in combination. Reaction temperature isnormally about -100° to 40° C., preferably about -80° to 25° C. Reactiontime is normally 5 minutes to 10 hours, preferably 10 minutes to 5hours. The amount of reducing agent used is normally 1 to 2 molequivalents per mol of compound (II). Also, of the compounds representedby formula (I) and (I'), a compound represented by the general formula:##STR78## wherein D' represents a C₁₋₃ alkylene group; the other symbolshave the same definitions as above or a salt thereof, can also beproduced by a reaction of a compound represented by the general formula:##STR79## wherein the symbols have the same definitions as above or asalt thereof, and a compound represented by the general formula:

    Ar--G'--CHO                                                (XVI)

wherein G' represents a bond or a C₁₋₂ alkylene group; the other symbolshave the same definitions as above, in the presence of a reducing agent.This reaction is carried out by various methods; for example, thereducing reaction described by R. F. Botch et al. in the Journal ofAmerican Chemical Society, Vol. 93, pp. 2897-2904 (published 1971) or amethod based thereon is preferably used. Also, a compound of generalformula (I) and (I') wherein D is a C₁₋₃ alkylene group and E is --NH--can be reacted with a carbonyl compound represented by the generalformula: ##STR80## wherein R⁵ p and R⁵ q, whether identical or not,independently represent hydrogen or an optionally substitutedhydrocarbon group, in the presence of a reducing agent, for example, theabove-mentioned method of Borch et al. or a method based thereon, toyield a compound or a salt thereof represented by the general formula:##STR81## wherein R^(5d) represents an optionally substitutedhydrocarbon group; the other symbols have the same definitions as above.

A compound of general formula (I-B), one of the desired compoundsdescribed above, which has a tricyclic structure, can, for example, beproduced by the following methods a) and b).

Method a)

A compound represented by the general formula: ##STR82## wherein jrepresents an integer from 0 to 2; the other symbols have the samedefinitions as above or a salt thereof or a reactive derivative thereofderivatized at the carboxyl group thereof (included in the desiredcompound of the present invention and produced by the above Method 1 or2) is cyclized by intramolecular amidation to yield a compoundrepresented by the general formula: ##STR83## wherein the symbols havethe same definitions as above or a salt thereof.

Method b)

A compound represented by the general formula: ##STR84## wherein D"represents --CH₂ -- or --CO--; L" represents a leaving group; krepresents an integer from 1 to 3; the other symbols have the samedefinitions as above (included in the desired compound of the presentinvention and produced by the above method 1 or 2) or a salt thereof, iscyclized by intramolecular alkylation to yield a compound or saltthereof represented by the general formula: ##STR85## wherein thesymbols have the same definitions as above or a salt thereof.

The above Method a), based on amide bond forming reaction, is carriedout by various procedures. For example, the same procedures as describedin method 1-i) may be used. Method b), based on alkylation, is carriedout by the s-me procedures as described in method 1-ii) or method 2 maybe used.

It is also possible to produce a compound of formula (I) wherein E is--NR^(5d) -- (the symbols have the same definitions as above) byalkylating a compound of formula (I) and (I') wherein E is --NH-- withan alkylating agent represented by the formula R^(5e) -L" (R^(5e)represents an optionally substituted alkyl group; L" represents aleaving group) by the same method as described in method 1-ii).

(iii) Of the compounds represented by the formula (I), a quinoline or anisoquinoline compound represented by the general formula: wherein--X^(b) --Y^(b) -- represents --N═CR³ -- or --CR³ ═N-- (R³ representsthe same meaning as defined above), E' represents --NR^(5f) --(R^(5f)represents an optionally ##STR86## substituted hydrocarbon group), --O--or --S(O)n--(n is 0, 1 or 2) and the other symbols are the same meaningas defined above, can be produced from a quinolone or an isoquinolonecompound represented by the general formula: ##STR87## wherein --X^(c)--Y^(c) -- represents --NH--CO-- or --CO--NH--, the other symbols arethe same meaning as defined above. This reaction is first conducted,preferably, by converting the amide moiety of (I^(g)) into the iminohalide group, yielding the compound (I^(f)) where R³ is a halogen atom(e.g. Cl, Br). The reagent used in the reaction is, for example,phosphorous halides such as phosphorous oxychloride, phosphorouspentachloride, and thionyl halides such as thionyl chloride, thionylbromide, etc. The amount of the reagent is 1 to 100 mol equivalentsrelative to the compound (I^(g)). The reaction is generally carried outin an inert solvent (e.g., ethers such as tetrahydrofurane, dioxane,hydrocarbons such as benzene, toluene, xylene), and the reagent itselfmay be used as the solvent. The reaction temperature is generally about20° C. to 200° C. and preferably 50° C. to 150° C. The reaction time,which depends on the species of starting compound, reagent, solvent andtemperature, is generally 30 minutes to 12 hours. The imino halide thusobtained can be converted to the compounds having various R³-substituent, i.e., a hydrogen atom, an optionally substitutedhydrocarbon group, an optionally substituted amino group, a substitutedhydroxyl group, or a mercapto group substituted by an optionallysubstituted hydrocarbon group. The compound (I^(f)) where R³ is ahydrogen atom can be prepared from (I^(f) ;R³ ═Cl, Br) by usingcatalytic reduction. The reduction can be carried out by a methodsimilar to that used in the conversion of (I^(b)) to (I^(a)). Thecompound (I^(f)) where R³ is an optionally substituted amino group canbe prepared from (I^(f) ;R³ ═Cl) by reacting an optionally substitutedamine under conditions similar to those used in the reaction of (XI) and(XII) (Method 1-ii). Similarly, the compound (I^(f)) where R³ is anoptionally substituted hydrocarbon group, a substituted hydroxyl groupor a mercapto group substituted by an optionally substituted hydrocarbongroup can be prepared from (I^(f) ;R³ ═Cl) by reacting a Grignardreagent (e.g., MeMgBr, EtMgBr), an alkaline metal (e.g., lithium,sodium, pottasium) salt of alchol (e.g., methanol, ethanol) or analkaline metal (e.g., lithium, sodium, pottasium) salt of thiol (e.g.,methanethiol, ethanethiol), respectively, under conditions similar to(Method 1-ii).

Of compound (I) and (I') of the present invention, a compound wherein Xor Y is a --CS-- group and/or D contains a thioxo group can be producedby reacting a compound wherein X or Y is a --CO-- group and/or Dcontains an oxo group with an appropriate sulfur containing reagents.Examples of such reagents include phosphorus pentasulfide and Lowesson'sreagent. This reaction is normally carried out in a solvent such asdichloromethane, chloroform, dioxane, tetrahydrofuran, benzene ortoluene under water-free conditions. The amount of sulfide used is notless than 1 mol equivalent, preferably 2 to 5 mol equivalents, reactiontemperature being between 20° C. and 120° C. Varying depending on kindof starting material or sulfide, reaction temperature etc., reactiontime is normally 1 to 8 hours.

When compound (I) and (I') or a salt thereof produced by the abovemethods contains a lower (C₁₋₆) alkoxy group on ring A (wherein ........is a double bond), ring B or the benzene ring in the group representedby Ar, it may be converted to a hydroxyl group as necessary by reactionwith, for example, boron tribromide. This reaction is normally carriedout in a solvent (e.g., halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, benzene and toluene,and hydrocarbons) at about -20° to 80° C., preferably about 0° to 30° C.The amount of boron tribromide used is about 1 to 10 mol equivalents,preferably about 1 to 5 mol equivalents per mol of lower alkoxy group.Reaction time is normally 15 minutes to 24 hours, preferably 30 minutesto 12 hours. Also, when compound (I) and (I') or a salt thereof producedby the above methods contains a hydroxyl group on ring A, ring B or thebenzene ring in the group represented by Ar, it may be converted to analkoxy or acyloxy group by alkylation or acylation as necessary. Thisalkylation is carried out by a reaction with an alkylating agent such asa halide (e.g., chloride, bromide, iodide) of an alkane which may have asubstituent or a sulfate ester or sulfonate ester (e.g.,methanesulfonate, p-toluenesulfonate, benzenesulfon-ate) in a solvent(e.g., alcohols such as methanol, ethanol and propanol, ethers such asdimethoxyethane, dioxane and tetrahydrofuran, ketones such as acetoneand amides such as N,N-dimethylformamide) in the presence of a base(e.g., organic bases such as trimethylamine, triethylamine,N-methylmorpholine, pyridine, picoline and N,N-dimethylaniline, andinorganic bases such as potassium carbonate, sodium carbonate, potassiumhydroxide and sodium hydroxide). Reaction temperature is normally -10°to 100° C., preferably about 0° to 80° C. The amount of these alkylatingagents used is about 1 to 5 mol equivalents, preferably 1 to 3 molequivalents per mol of starting material phenolic derivative. Reactiontime is normally 15 minutes to 9.4 hours, preferably 30 minutes to 12hours.

Acylation is carried out by using the appropriate carboxylic acid or areactive derivative thereof. Although varying depending on type ofacylating agent and type of starting material phenolic derivative, thisreaction is normally carried out in a solvent (e.g., hydrocarbons,ethers, esters, halogenated hydrocarbons, amides, aromatic amines suchas benzene, toluene, ethyl ether, ethyl acetate, chloroform,dichloromethane, dioxane, tetrahydrofuran, N,N-dimethylformamide andpyridine); appropriate bases (e.g., hydrogen carbonates such as sodiumhydrogen carbonate and potassium hydrogen carbonate, carbonates such assodium carbonate and potassium carbonate, acetates such as sodiumacetate, tertiary amines such as triethylamine, aromatic amines such aspyridine) may be added to accelerate the reaction. Such reactivederivatives of carboxylic acid include acid anhydrides, mixed acidanhydrides and acid halides (e.g., chloride, bromide). The amount ofthese acylating agents used is 1 to 5 mol equivalents, preferably 1 to 3mol equivalents per mol of starting material phenolic derivative.Reaction temperature is normally about 0° to 150° C., preferably about10° to 100° C. Reaction time is normally 15 minutes to 12 hours,preferably 30 minutes to 6 hours.

Also, known amide compounds of formula (I) and (I') can be synthesizedby, for example, (1) the method described in the Indian Journal ofChemistry, Section B, 26B, Vol. 8, pp. 744-747 (published 1987), (2) themethod described in the Chemical Abstract, Vol. 107, 175835f, (3) themethod described in the Chemical Abstract, Vol. 114, 42492q, (4) themethod described in the Chemical Abstract, Vol. 107, 115463y, (5) themethod described in the Chemical Abstract, Vol. 93, 220536q, a methodbased thereof, or by the above-described production method for thecompounds represented by formula (I) and (I') or methods based thereon.

When compound (I) and (I') is obtained in a free form by one of theabove methods, it may be prepared as a salt with an inorganic acid(e.g., hydrochloric acid, sulfuric acid, hydrobromic acid), an organicacid (e.g., methanesulfonic acid, benzenesulfonic acid, toluenesulfonicacid, oxalic acid, fumaric acid, maleic acid, tartaric acid), aninorganic base (e.g., alkali metals such as sodium and potassium,alkaline earth metals such as calcium and magnesium, aluminum orammonium), or an organic base (e.g., trimethylamine, triethylamine,pyridine, picoline, ethanolamine, diethanolamine, triethanolamine,dicyclohexylamine or N,N'-dibenzylethylenedismine). When compound (I) isobtained in the form of a salt, it can be converted to the free form oranother salt, in accordance with a conventional method.

The thus-obtained desired compound (I) and (I') or salt thereof can bepurified and separated by a known means of separation and purification(e.g., concentration, solvent extraction, column chromatography orrecrystallization).

Starting material (VII), or a salt thereof, used to produce theinventive compound (I) and (I') or a salt thereof can industriallyadvantageously produced by, for example, the following methods 1) to 3)or methods based thereon.

1) Compounds represented by the general formulas: ##STR88## wherein thesymbols have the same definitions as above, or esters thereof can besynthesized by methods (or methods based thereon) such as thosedescribed in European Patent Publication No. 421456 (published Apr. 11,1991), European Patent Publication No. 354994 (published Feb. 21, 1990),European Patent Publication No. 481383 (published Apr. 22, 1992), PCTInternational Patent Publication No. WO9112249 (published Aug. 22,1991), and Bolletino Chimico Farmaceutico, vol. 125 pp. 437-440(published 1986, describe dy N. A. Santagati et al.).

The compound (VII-3) can also be produced via an amide compound of(VII-3). An amide compound of (VII-3) is produced by the methoddescribed by K. Unverferth et al. in Archiv der Pharmazie, Vol. 324,pp.809-814 (published 1991) or a method based thereon. This amide compoundmay be reacted under, for example, diazotizing conditions (e.g., reactedwith sodium nitrite at about 0° to 50° C. in an acidic solvent such asacetic acid or hydrochloric acid) to yield compound (VII-3).

2) Compounds represented by the general formulas: ##STR89## wherein thesymbols have the same definitions as above, can be synthesized by, forexample, the following methods 2-A) and 2-B) or methods based thereon.

Method 2-A)

The carboxyl group of (VII-1) to (VII-5) is treated with diazomethane toadd one carbon atom to the carboxyl group by a reaction generally knownas the Arndt-Eistert reaction (F. Arndt et al.: Chemische Berichte, Vol.68, page 200 (published 1935)) to yield (VII-6) to (VII-10),respectively. For example, a method is known wherein a compound offormula (VII-5) whose ring A is not substituted for and whose ring B isnot substituted for or has substituent methyl for R³ in the aboveformula is converted to a corresponding compound of formula (II-10)having a substituent (I. N. Chatterjea et al.: Liebigs Ann. Chem., 1974,page 1126); by this method or a method based thereon, (VII-6) to(VII-10) can be produced. In this method, the desired compound may beisolated as a carboxylic acid ester (methyl ester, ethyl ester etc.),which ester is then converted to a carboxylic acid by hydrolysis. Thishydrolyzing reaction is normally carried out in a solvent (e.g.,alcohols such as methanol, ethanol and propanol, organic acids such asacetic acid) in the presence of an aqueous solution of a mineral acid(e.g., hydrochloric acid, hydrobromic acid, sulfuric acid) or a metalhydroxide (e.g., sodium hydroxide, potassium hydroxide) at a treatmenttemperature of about 15° to 103° C.

Method 2-B)

One carbon atom is also added to the carboxyl group of (VII-1) to(VII-5) by the following method: ##STR90## wherein H represents theheterocyclic moiety of (VII-1) to (VII-10); L represents a leavinggroup. In this method, the carboxyl group is first reduced to yield analcohol. This reduction is carried out by converting the carboxyl groupto a reactive derivative thereof (acid halide, mixed acid anhydride,active ester, ester etc.) and then treated at a reaction temperature ofabout 0° to 100° C. in a solvent (ether such as tetrahydrofuran ordimethoxyethane) in the presence of a reducing agent (sodiumborohydride, lithium aluminum hydride). The hydroxyl group of thethus-obtained alcohol is converted to a leaving group (--OH→--L). Theleaving group L is preferably a halogen (chlorine, bromine, iodineetc.), a C₁₋₄ alkanesulfonyloxy group (e.g., methanesulfonyloxy group,ethanesulfonyloxy group) or a C₆₋₁₀ arylsulfonyloxy group (e.g.,benzenesulfonyloxy group, p-toluenesulfonyloxy group). This convertingreaction is normally carried out by a treatment with, for example,thionyl chloride, thionyl bromide, methanesufonyl chloride orbenzenesulfonyl chloride in a solvent (e.g., benzene, toluene,dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, ethylacetate) at a treatment temperature of about 0° to 100° C. The leavinggroup of the compound is then converted to a nitrile group (--L→--CN).This reaction is normally carried out by a treatment with, for acyanogen compound such as sodium cyanide, potassium cyanide or coppercyanide in a solvent (e.g., dimethylsulfoxide, dimethylformamide,acetone) at a treatment temperature of 0° to 100° C. The resultingnitrile compound is hydrolyzed to carboxylic acids (VII-6) to (VII-10).This hydrolyzing reaction is normally carried out in a solvent (alcoholsuch as methanol, ethanol or propanol, or acetic acid) in the presenceof an aqueous solution of a mineral acid (e.g., hydrochloric acid,hydrobromic acid, sulfuric acid) or a metal hydroxide (e.g., sodiumhydroxide, potassium hydroxide) at a treatment temperature of about 15°to 130° C. Compounds (VII-6) and (VII-7) can also be produced by themethod described by H. Kohl et al. in the Journal of PharmaceuticalSciences, Vol. 69, page 2028 (published 1973) or a method based thereon.

3) Compounds represented by the general formulas: ##STR91## wherein thesymbols have the same definitions as above, can be produced from theabove compounds (VII-1), (VII-3), (VII-4), (VII-5) or esters thereof,respectively, by reducing the double bond at the positions 3 and 4 tosingle bond. This method can, for example, be carried out by theabove-described method used to convert (I^(a)) to (I^(b)) or a methodbased thereon. When an ester is used as the starting material, esters of(VII-11) to (VII-14) are produced, which may be hydrolyzed as describedin Method 2-A) to carboxylic acids. Compound (VII-11) or an esterthereof can also be produced using a reducing agent such as lithiumaluminum hydride. This reaction is normally carried out in a solvent(ethers such as tetrahydrofuran, dioxane and dimethoxyethane) at atemperature of about 0° to 100° C.

4) A compound represented by the general formula: ##STR92## wherein thesymbols have the same definitions as above, can be produced from, forexample, compound (VII-2A) by the following method: ##STR93## wherein R'represents a lower alkyl group (e.g. methyl, ethyl, etc.), the othersymbols having the same definitions as above.

In this method, (VII-2A) is first reduced, at the positions 1 and 4, toa 1,4-dihydro derivative. This reducing reaction is carried out using areducing agent such as sodium borohydride or sodium cyanoborohydride.The reaction is normally carried out in a solvent (alcohols such asmethanol, ethanol and propanol, ethers such as tetrahydrofuran, dioxaneand dimethoxyethane) at a temperature of about 15° to 100° C. Theposition 1 of this 1,4-dihydro derivative is then alkylated by areaction with an alkylating agent represented by the general formulaR'--L (the symbols have the same definitions as above). The alkylatingreaction is normally carried out in a solvent (ethers such astetrahydrofuran, dioxane and dioxane, amides such as dimethylformamide),preferably in the presence of a base (e.g., sodium hydride, potassiumhydride, sodium methylate, sodium ethylate, sodium amide, potassiumt-butoxide). The reaction is normally carried out at a temperature ofabout -10° to 100° C. The thus-obtained 1-alkyl-1,4-dihydro derivativeis reduced to a 1,2,3,4-tetrahydro derivative (VII-15A). This reducingreaction is carried out using a reducing agent such as sodiumcyanoborohydride, sodium borohydride or lithium aluminum hydride. Thereaction is normally carried out in a solvent at a temperature of about0° to 100° C. Varying depending on the kinds of reducing agent andsubstrate used, it is possible to use the same solvents as used in theabove-described reducing reaction of (VII-2A) to 1,4-dihydro derivative.Conversion of (VII-15A) to (VII-15) is achieved by a hydrolyzingreaction as described in Method 2-A).

5) Compounds represented by the general formulas: ##STR94## wherein thesymbols have the same definitions as above, can be produced from theabove-mentioned compounds (VII-11) to (VII-15) by adding one carbonatom. This method can be carried out in the same manner as theabove-described Method 2-A) or 2-B) or a method based thereon. (VII-16)and (VII-19) can also be produced by the following method: ##STR95##wherein X⁰ represents --NR^(1a) -- (R^(1a) represents the same meaningas defined hereinabove) or --O--; R" and R'" independently represent aprotecting group for the carboxyl group; the other symbols have the samedefinitions as above.

With respect to the above formula, the carboxyl group protecting groupsR" and R'" is exemplified by ester-forming protecting groups such asmethyl, ethyl, methoxymethyl, methoxyethoxymethyl, benzyloxymethyl,tert-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, o-nitrobenzyl,benzhydryl, trityl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl andallyl, and silyl-ester-forming protective groups such as trimethylsilyl,triethylsilyl, tert-butyldimethylsilyl, isopropyldimethylsilyl anddimethylphenylsilyl. In the above method, the position 3 of (VII-11A) or(VII-13A) is first alkylated with an alkylating agent represented by thegeneral formula R'"OCOCH₂ -L (the symbols have the same definitions asabove). This reaction can be carried out under the same conditions asfor the position 1 alkylation in 4) above. The resulting alkylderivative, after removal of the protecting group R", may bedecarboxylated to (VII-16A) or (VII-19A). Varying depending on the typeof protecting group used, the protecting group R" can be removed byhydrolysis by the method described in Method 2-A) above when R" is alower alkyl group such as methyl or ethyl. In this case, when R'" issimilarly a lower alkyl group such as methyl or ethyl, it may also beremoved to leave and isolate a dicarboxylic acid. While heating, theR"-removed carboxylic acid may be further decarboxylated to yieldcompound (VII-16A) or (VII-19A). In the case of a dicarboxylic acidwherein both R" and R'" have been removed, this decarboxylationimmediately results in the production of (VII-16) or (VII-19). Thisdecarboxylation is normally carried out in a solvent (e.g., pyridine,picoline, benzene, toluene, dimethylsulfoxide, dimethylformamide, aceticacid) at a temperature of about 40° to 200° C. The thus-obtainedcompounds (VII-16A) and (VII-19A) can be converted to compounds (VII-16)and (VII-19), respectively, by removing their R'" by a deprotectingreaction according to the type thereof.

6) A compound represented by the general formula: ##STR96## whereinX^(d) represents --NR^(1a) -- (R^(1a) represents the same meaning asdefined hereinabove), --O-- or --S--; Z" represents --CR^(4a) -- (R^(4a)is an optionally substituted hydrocarbon group) or --N--; the othersymbols have the same definitions as above, is produced by alkylating acompound represented by the general formula: ##STR97## wherein thesymbols have the same definitions as above, with the alkylating agentused above 5), represented by the formula R'"OCOCH₂ -L, and thenremoving the protecting group R'". The alkylating and deprotectingreactions can be carried out under the same conditions as describedabove.

7) Compounds (VII'-23) and (VII'-24), represented by the generalformula: wherein the symbols have the some definitions as above, andhaving --NR^(1a) -- for X^(d) and hydrogen for at least one of R² andR^(2a), can be produced by the following method: ##STR98## wherein thesymbols have the same definitions as above. In this method, (VII-2A) or(VII-7A) is first alkylated to a quaternary salt, which is then reducedto a 1,2-dihydro derivative (VII-23A) or (VII-24A), respectively. Thisconverting reaction can be carried out in the same manner as theconverting reaction of compound (I^(d))→(I^(e))→(I^(c)). Thethus-obtained compounds (VII-23A) and (VII-24A) may be subjected to theabove-described Method 2-A) to remove R' to yield (VII-23) and (VII-24),respectively.

Alternatively, (II-23) can be produced by the following method:##STR99## wherein the symbols have the same definitions as above. Inthis method, a benzophenone derivative, as the starting material, isreacted with, for example, a propionic acid derivative represented bythe following formula: ##STR100## wherein the symbols have the samedefinitions as above, to a substituted benzophenone derivative. Upondehydrating reaction, this compound yields a cyclized derivative(VII-23A). (VII-23A) may be subjected to the above-described Method 2-A)to remove R' to yield (VII-23).

(VII-23) may be subjected to the above-described Method 2-A) or 2-B) toadd one carbon atom to yield (VII-24).

8) Compounds represented by the general formula: ##STR101## wherein thesymbols have the same definitions as above, and having S for X^(d),hydrogen for each of R² and R^(2a) and 0 for p, include known compounds;for example, Natsugari et al. describe in European Patent PublicationNo. 481383 (published Apr. 22, 1992) a method of synthesizing thesecompounds as intermediates. Another compound (VII-25) wherein p═0 canalso be produced in accordance with this method. (VII-25) may be treatedin the same manner as the above-described Method 2-A) or 2-B) to add onecarbon atom to yield (VII-26).

9) A compound represented by the general formula: ##STR102## wherein thesymbols have the same definitions as above, can be produced from, forexample, compounds of formulas (VII-6) to (VII-10), (VII-16) to(VII-22), (VII-24) and (VII-26) by adding one carbon atom by theabove-described reaction Method 2-A) or 2-B).

10) In accordance with the above-described methods 1) through 3), 5) and9), compounds of general formula (VII) wherein either X' or Y'-- is S,the other being --CO--, can be produced. Also, compounds of generalformula (VII) wherein either X' or Y' is --CO-- can be converted tothose wherein either is --CS-- by a thioxo-derivatizing reaction withphosphorus pentasulfide etc.

11) A compound represented by the general formula: ##STR103## wherein αrepresents an integra from 1 to 3, the other symbols representing thesame definition as above, can be produced from the correspondingcarboxylic acid by subjecting reduction as described in Method 2B).

12) A compound represented by the general formula: ##STR104## whereinthe symbols represent the same definition as above can be produced fromthe corresponding hydroxyl compound (XIV) by subjecting the conversion(--OH→--L) reaction described in Method 2B).

13) A compound represented by the general formula: ##STR105## whereinthe symbols represent the same definition as above can be produced from(XV) by reacting an amine represented by the formula R⁵ --NH₂ (thesymbols have the same definition as above). This reaction can be carriedout using the same conditions as those described in the alkylationreaction of (II) with (III) (Method 1-ii).

When the substituent in these compounds thus prepared contains afunctional group, it can be converted to another appropriate functionalgroup by various known methods. For example, when the substituent is agroup containing a carboxyl group or ester thereof, it can be convertedto an amide group by reaction with, for example, an amine or to ahydroxymethyl group or another group by reduction, for a startingmaterial for synthesis of compound (I) and (I').

Starting materials for production of compound (I-A) or a salt thereofinclude compounds represented by the formulas (S-1) and (S-2). Thesecompounds can be produced by the method schematized in the followingreaction scheme 1 or a method based thereon. ##STR106## wherein P¹ andP² independently represent a protecting group for the carboxyl group; trepresents an integer from 2 to 4; the other symbols have the samedefinitions as above.

With respect to the above formulas, the carboxyl group protecting groupsP¹ and P² are exemplified by ester-forming protecting groups such asmethyl, ethyl, methoxymethyl, methoxyethoxymethyl, benzyloxymethyl,tert-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, o-nitrobenzyl,benzhydryl, trityl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl andallyl, and silyl-ester-forming protective groups such as trimethylsilyl,triethylsilyl, tert-butyldimethylsilyl and isopropyldimethylsilyl.

In the above method, compound (S-a) is first intramolecularly cyclizedto compound (S-b). This cyclization is carried out by a reactiongenerally known as Dieckmann Condensation J. P. Schaefer et al.: OrganicReactions, Vol. 15, pp. 1-203 (published 1967)! in a solvent inert tothe reaction (e.g., tetrahydrofuran, dioxane, dimethoxyethane) in thepresence of a base (e.g., sodium hydride, sodium ethoxide, sodiummethoxide, sodium amide, potassium tert-butoxide). The amount of baseused is not less than 1 mol equivalent, preferably 1.5 to 3 molequivalents per mol of (S-a), reaction temperature being between about0° C. and 130° C. Varying depending on type of starting materialcompound, reaction temperature and other factors, reaction time isnormally about 0.5 to 5 hours.

The protected carboxyl group of compound (S-b) is removed to yieldketone compound (S-c). This reaction can be carried out under varioussets of conditions depending on type of the protecting group P¹ used;when P¹ is a lower alkyl group such as methyl or ethyl, acidic oralkaline hydrolytic conditions are preferably used, under whichdecarboxylation usually takes place simultaneously with the removal ofP¹, yielding compound (S-c). This reaction is carried out in a solvent(e.g., alcohols such as methanol, ethanol and propanol, ethers such astetrahydrofuran, dioxane and dimethoxyethane, and mixtures thereof)under alkaline conditions with an alkali such as sodium hydroxide orbarium hydroxide or an alkaline earth metal hydroxide or under acidicconditions with an inorganic acid such as hydrochloric acid, bromic acidor sulfuric acid or with an organic acid such as formic acid or aceticacid, or a mixture of these acids. Reaction temperature is normallyabout 0° to 150° C., preferably about 15° to 110° C., reaction timebeing about 0.5 to 24 hours, preferably about 1 to 10 hours.

Conversion of compound (S-c) to amino compound (S-1) is preferablyachieved by a method of oxime derivative reduction. In this method,compound (S-c) is first reacted with hydroxylamine to yield an oximecompound by a conventional method (e.g., reacted at 20° to 70° C. inethanol in the presence of hydroxylamine hydrochloride and sodiumacetate). This oxime compound is then reduced to compound (S-1). Thisreducing reaction is carried out by, for example, the method describedby C. A. Buehler et al. in the Survey of Organic Syntheses, pp. 423-424(1970, published by Wiley-Interscience). For example, a reducingreaction with zinc powder is conducted under acidic conditions (e.g., inacetic acid solvent) or basic conditions (e.g., in a mixed solvent ofethanol and aqueous ammonia in the presence of ammonium acetate).

Hydroxyl compound (S-2) is produced by reducing compound (S-c). For thisreducing reaction, a reducing agent such as sodium cyanoborohydride orsodium borohydride is preferably used. The reaction is carried out in asolvent (e.g., methanol, ethanol, tetrahydrofuran, dioxane,dimethoxyethane) at a temperature of about 0° to 50° C., the reactiontime being about 15 minutes to 5 hours.

Each of the above compounds thus prepared as the starting material mayform a salt. Such salts include those with inorganic acids (e.g.,hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid) andthose with organic acids (e.g., acetic acid, formic acid, propionicacid, fumaric acid, maleic acid, succinic acid, tartaric acid, citricacid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid,benzenesulfonic acid). When these compounds have an acidic group such as--COOH, they may form a salt with an inorganic base (e.g., alkali metalor alkaline earth metals such as sodium, potassium, calcium andmagnesium, ammonia) or with an organic base (e.g., tri-C₁₋₃ alkylaminessuch as triethylamine).

The compounds obtained by the above methods may be purified andcollected by known methods of purification such as concentration, liquidphase conversion, re-dissolution, solvent extraction, columnchromatography, crystallization and recrystallization, or may be used inthe form of a mixture as such for the subsequent reaction.

When the starting material compound used in the above reactions containsan amino group, a carboxyl group or a hydroxyl group as a substituent,these groups may have incorporated a protecting group generally used inpeptide chemistry and other fields; the desired compound can be obtainedby removing the protecting group as necessary after completion of thereaction.

Amino group protecting groups include C₁₋₆ alkylcarbonyl groups whichmay have a substituent (e.g., formyl, methylcarbonyl, ethylcarbonyl),phenylcarbonyl groups, C₁₋₆ alkyl-oxycarbonyl groups (e.g.,methoxycarbonyl, ethoxycarbonyl), phenyloxycarbonyl groups (e.g.,benzoxycarbonyl), C₇₋₁₀ aralkyl-carbonyl groups (e.g.,benzyloxycarbonyl), trityl and phthaloyl. Substituents for theseprotecting groups include halogen atoms (e.g., fluorine, chlorine,bromine, iodine), C₁₋₆ alkyl-carbonyl groups (e.g., methylcarbonyl,ethylcarbonyl, butylcarbonyl) and nitro groups, the number ofsubstituents being 1 to 3.

Carboxyl group protecting groups include C₁₋₆ alkyl groups which mayhave a substituent (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl,tert-butyl), phenyl, trityl and silyl. Substituents for these protectinggroups include halogen atoms (e.g., fluorine, chlorine, bromine,iodine), C₁₋₆ alkylcarbonyl groups (e.g., formyl, methylcarbonyl,ethylcarbonyl, butylcarbonyl) and nitro groups, the number ofsubstituents being 1 to 3.

Hydroxyl group protecting groups include C₁₋₆ alkyl groups which mayhave a substituent (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl,tert-butyl), phenyl groups, C₇₋₁₀ aralkyl groups (e.g., benzyl), C₁₋₆alkylcarbonyl groups (e.g., formyl, methylcarbonyl, ethylcarbonyl),phenyloxycarbonyl groups (e.g., benzoxycarbonyl), C₇₋₁₀ aralkyl-carbonylgroups (e.g., benzyloxycarbonyl), pyranyl groups, furanyl groups andsilyl groups. Substituents for these protecting groups include halogenatoms (e.g., fluorine, chlorine, bromine, iodine), C₁₋₆ alkyl groups,phenyl groups, C₇₋₁₀ aralkyl groups and nitro groups, the number ofsubstituents being 1 to 4.

Protecting groups can be removed by known methods or those basedthereon, including treatments with acids, bases, reducing agents,ultraviolet rays, hydrazine, phenylhydrazine, sodiumN-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetateetc.

The thus-obtained compound (I) and (I') can be isolated and purified byordinary means of separation such as recrystallization, distillation andchromatography. When compound (I) and (I') is obtained as a free form,it can be converted to a salt by a known method or a method basedthereon (e.g., neutralization). Contrarily, when it is obtained as asalt, it can be converted to a free form or another salt by a knownmethod or a method based thereon.

When compound (I) and (I') has a chiral center(s), it can be resolved tod- and 1-configurations by conventional methods of optical resolution.

The compound (I) and (I') or a salt thereof is low in acute toxicity(Mice are dosed at 300 mg/kg, p.o. and 100 mg/kg, i.p. for observationof acute toxic sympotoms or autonomic effects during the subsequent 72hours; the response is no effect) and chronic toxicity, thus being amedicinally useful and safe substance.

The compounds (I) and (I') or a pharmacologically acceptable saltthereof (e.g., the above-mentioned salts with inorganic or organic basesand salts with inorganic or organic acids) exhibit excellent inhibitoryaction against acyl-CoA:cholesterol acyl transferase (ACAT), and ispharmaceutically safe with low acute and chronic toxicities. ACAT, anenzyme involved in the higher fatty acid esterification of cholesterolin cells, is known to play a key role in cholesterol ester absorption inthe digestive tract and cholesterol ester accumulation in variousperipheral organs and cells (e.g., arterial walls, macrophages).ACAT-inhibiting substances can therefore inhibit intestinal absorptionof food cholesterols to suppress blood cholesterol level rise andsuppress intracellular cholesterol ester accumulation inarteriosclerosis lesions, thus preventing progress of atherosclerosis.The objected compounds or salt thereof of the present invention,exhibiting such excellent ACAT-inhibitory action and excellentcholesterol-lowering activity, is therefore useful as a safepreventive/therapeutic agent for hypercholesterolemia, atheromatousarteriosclerosis and diseases associated therewith (e.g. ischemicdiseases such as myocardial infarction and cerebrovascular diseases suchas cerebral infarction and cerebral stroke) in mammals (e.g., mice,rats, hamsters, rabbits, cats, dogs, horses, bovines, sheep, monkeys,humans).

Also, the compounds (I) and (I') or salt thereof include those whichexhibit suppressing action against lipid peroxide production(antioxidant action) (e.g., compound of the above formula wherein atleast one of rings A, B and Ar is a benzene ring substituted by an aminoor hydroxyl group which may be substituted by a C₁₋₄ alkyl group). Lipidperoxidation in vivo is known to be closely associated with the onset ofarteriosclerosis and ischemic diseases in the brain and cardiovascularsystem. Accordingly, the objected compound (I) and (I') or salt thereof,which exhibits both ACAT inhibitory and antioxidant actions, is highlyuseful as a pharmaceutical, because it can prevent and treat variousvascular lesions due to these changes for both blood cholesterol andperoxide lipid.

When the compounds (I) and (I') or a pharmacologically acceptable saltthereof is used as a pharmaceutical as described above, it can be orallyor non-orally administered in the form of powder, fine subtilaes,granules, tablets, capsules, injectable solutions or other dosage formsby conventional methods in a mixture with appropriate pharmacologicallyacceptable carriers, excipients (e.g., starch, lactose, sucrose, calciumcarbonate, calcium phosphate), binders (e.g., starch, gum arabic,carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose,alginic acid, gelatin, polyvinylpyrrolidone), lubricants (e.g., stearicacid, magnesium stearate, calcium stearate, talc), disintegrating agents(e.g., carboxymethyl cellulose calcium, talc), diluents (e.g.,physiological saline) and other additives. However, for inhibitingcholesterol absorption, oral administration is preferred. Varyingdepending on type of the objected compound or salt thereof, route ofadministration, symptoms, patient's age etc., daily dose is about 0.005to 50 mg, preferably about 0.05 to 10 mg, more preferably about 0.2 to 4mg per kg body weight for oral administration in adulthypercholesterolemia patients. This daily dose is preferablyadministered in one to three portions.

The compounds (I) and (I') of the present invention or a salt thereofexhibit excellent ACAT-inhibitory action and excellentcholesterol-lowering activity. The results of a pharmacologic testthereof are given below.

The following data of (I) to (III) are the experimental data showing thepharmacological efficacy of the compound (I) and (I') or salts thereofof the present invention.

(I) Inhibitory Action Against Acyl-CoA:cholesterol Acyl Transferase(ACAT) Method of Experiment

An ACAT enzyme preparation was prepared from a small intestine mucosalmicrosome fraction of a 6-week-old male Sprague-Dawley rat, previouslyfasted for 20 hours, in accordance with the method described by Heideret al. in the Journal of Lipid Research, Vol. 24, page 1127 (1982).

ACAT activity was determined by measuring the amount of labeledcholesterol ester produced from 1-¹⁴ C!-oleoyl-CoA and endogenouscholesterol, in accordance with the method of Helgerud et al. Journal ofLipid Research, Vol. 22, page 271 (1981)!.

Results

(1) Table 1 shows data on the inhibitory rate (%) of formation oflabeled cholesterol ester inhibitory rate (%), as an index ofACAT-inhibitory action, obtained when the compound was added at 10⁻⁶ M.

                  TABLE 1                                                         ______________________________________                                        Subject Compound                                                                            ACAT Inhibitory Rate (%)                                        (Example No.) 10.sup.-6 M                                                     ______________________________________                                         9            90.3                                                            10            93.3                                                            13            93.8                                                            15            90.2                                                            18            97.3                                                            19            99.1                                                            20            97.8                                                            21            99.3                                                            22            97.9                                                            23            99.4                                                            25            96.9                                                            27            92.0                                                            29            98.4                                                            31            97.5                                                            32            96.0                                                            33            98.9                                                            36            98.8                                                            42            96.6                                                            43            98.2                                                            45            99.5                                                            47            90.3                                                            48            99.2                                                            49            92.8                                                            50            95.7                                                            51            98.1                                                            52            90.4                                                            53            99.7                                                            54            98.4                                                            55            97.9                                                            56            98.1                                                            57            99.3                                                            60            99.9                                                            64            99.5                                                            74            99.5                                                            76            99.3                                                            79            99.1                                                            82            99.3                                                            83            99.4                                                            84            99.5                                                            85            99.5                                                            87            99.3                                                            88            99.7                                                            89            98.2                                                            92            98.2                                                            93            99.0                                                            94            98.6                                                            95            99.1                                                            96            99.3                                                            99            97.0                                                            ______________________________________                                    

Table 1 shows that compound (I) or a salt thereof exhibits excellentACAT-inhibitory action.

(II) Hypocholesterolemic Activity (Cholesterol-lowering Activity) Methodof Experiment

Groups of 6 ICR mice (2 subgroups of 3 mice) were madehypercholesterolemic by being fed a high cholesterol-cholic acid dietfor 7 days and administered with test compounds orally on the last twodays. One-half of the total does was given on day 6 followed by theother half on day 7. After fasting overnight (16 hours after the lastdose), the animals were sacrificed and sera were collected together forthe each subgroup for measuring the levels of cholesterol and heparinprecipitating lipoproteins (HPL). Both cholesterol and HPL levels weremeasured with autonalyzer by the enzymatic CHOD-PAP method for theformer and by the turbidimetric method of Shurr et. al. in C. E. Dau ed.Atherosclerosis Drug Discovery, Plenum Publishing, New York, pp. 215-229& 231-249, 1976.! for the latter.

Table 2 shows reduction % (compared to control groups) of cholesteroland HPL.

Results

                  TABLE 2                                                         ______________________________________                                        Test compounds                                                                            Dose (po)    Reduction %                                          (Example No.)                                                                             mg/kg        cholesterol                                                                            HPL                                         ______________________________________                                        48          10           32       39                                                       3           27       26                                          74          10           33       37                                                       3           29       32                                          82          10           40       50                                                       3           31       37                                          84          10           33       47                                                       3           15       28                                          ______________________________________                                    

From Table 2, it is clear that compound (I) or a salt thereof exhibitsexcellent hypocholesterolemic activity.

Also, the compounds (I) and (I') and a salt thereof according to theinvention has excellent tachykinin receptor antagonizing activity,particularly potent antagonistic activity against substance P(hereinafter sometimes referred to briefly as SP), and is low in acutetoxicity and chronic toxicity, thus being a medicinally useful and safesubstance.

Substance P (SP) is a neuropeptide discovered in an equine intestinalcanal extract in 1981 and its structure, consisting of 11 amino acids,was established in 1971. SP is broadly distributed in the central andperipheral nervous systems and, in addition to being a primary sensoryneurotransmitter, has various physiological activities such asvasodilating activity acugmentation of vascular permeability, smoothmuscle contracting activity, neuronal excitatory activity, sialogogueactivity, facilitation of micturition and immunomodulatory effect. It isknown particularly that SP released by a pain impulse at the terminal ofthe cornu posterius of the spinal cord transmits pain information tosecondary neurons and that SP released from the peripheral nerveterminal induces an inflammatory response in the nociceptive field.Moreover, SP is suspected to be involved in Alzheimer type dementia.Therefore, the objected compounds or salts thereof having potent SPreceptor antagonizing activity are of value as a safeprophylactic/therapeutic drug for pain, inflammation, allergy airwaydiseases such as asthma and cough, disturbances of micturition such aspollakiuria and incontinence dementia in mammalian animals (e.g. mouse,rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, man, etc.).

The dosage is dependent on the species of the objected compound or saltsthereof, route of administration, disease condition, and patient's ageand other background factors. However, for oral administration to anadult patient, for instance, a daily dose of about 0.0015 to 50 mg,preferably about 0.05 to 10 mg, more preferably about 0.2 to 4 mg, perkg body weight is administered in 1 to 8 divided doses.

(III) Radioligand Receptor Binding Inhibitory Assay Using Receptor FromHuman Lymphoblast Cells (IM-9)

The method of A. Margaret et al. Molecular Pharmacology 42, 458 (1992)!was modified and used. The receptor was prepared from human lymphoblastcells (IM-9). IM-9 cells were grown in 175 cm² tissue culture flasks(100 ml×10) at a density approximately 2×10⁵ /ml of RPMI 1640 withL-glutamine, 10% (V/V) heat inactivated fetal calf serum, penicillin(100 u/ml), and streptomycin (100 μg/ml) at 37° C. in 5% CO₂ /95% airfor 3 days. IM-9 cells were obtained by centrifugation at 500 Xg for 5minutes at 5° C. The pellet obtained was washed once with phosphatebuffer (Flow Laboratories, CAT No. 28-103-05), homogenized usingPolytron homogenizer (Kinematika, Germany) in 30 ml of 50 mM Tris-HClbuffer containing 120 mM NaCl, 5 mM KCl, 2 μg/ml phenylmethyl sufonylfluoride, and 1 mM ethylenediamine tetra-acetic acid and thencentrifuged at 40,000 Xg for 20 minutes. The residue was washed twicewith 30 ml of buffer described above, and preserved frozen (-80° C.).

The above specimen was suspended in a reaction buffer (50 mM Tris-HClbuffer (pH 7.4), 0.02% bovine serum albumin, 1 mM phenylmethylsulfonylfluoride, 2 μg/ml chymostatin, 40 μg/ml bacitracin, 3 mM manganesechloride) at a protein concentration of 1.5 mg/ml and a 100 μl portionof the suspension was used in the reaction. After addition of the sampleand 125I-BHSP (0.46 KBq), the reaction was conducted in 0.2 ml ofreaction buffer at 25° C. for 30 minutes. The amount of nonspecificbinding was determined by additing substance P at a final concentrationof 2×10⁻⁶ M. After the reaction, using a cell harvester (290PHD,Cambridge Technology, Inc., England), rapid filtration was carried outthrough a glass filter (GF/B, Whatman, U.S.A.) to stop the reaction.After washing three times with 250 μl of 50 mM Tris-HCl buffer (pH 7.4)containing 0.02% bovine serum albumin, the radioactivity remaining onthe filter was measured with a gamma counter. Before use, the filter wasimmersed in 0.1% polyethyleneimine for 24 hours and air-dired.

The antagonistic activity of each test substance, in terms of theconcentration necessary to cause 50% inhibition IC₅₀ ! under the aboveconditions, was expressed in nM (Table 3).

                  TABLE 3                                                         ______________________________________                                        Test Compounds                                                                Example No.     IC50 (nM)                                                     ______________________________________                                        101             2.5                                                           102             1.3                                                           103             34                                                            104             16                                                            105             19                                                            106             30                                                            107             34                                                            108             30                                                            109             50                                                            110             90                                                            111             98                                                            112             8.4                                                           122             82                                                            123             46                                                            127             8.8                                                           128             88                                                            130             38                                                            131             86                                                            156             6.1                                                           157             1.2                                                           158             78                                                            159             12                                                            165             24                                                            166             0.35                                                          170             19                                                            171             20                                                            172             0.5                                                           173             24                                                            174             3.4                                                           175             6.2                                                           176             0.7                                                           177             13                                                            178             0.14                                                          179             80                                                            180             9.1                                                           181             31                                                            182             2                                                             184             17                                                            185             32                                                            186             1.8                                                           187             1.4                                                           188             1.2                                                           189             1.7                                                           190             13                                                            191             28                                                            205             22                                                            207             110                                                           208             140                                                           211             23                                                            212             30                                                            216             62                                                            218             23                                                            221             130                                                           224             68                                                            225             94                                                            233             44                                                            239             80                                                            240             2                                                             241             60                                                            242             8.6                                                           243             0.9                                                           244             1.6                                                           245             59                                                            246             0.61                                                          247             5.2                                                           248             16                                                            249             17                                                            250             0.9                                                           251             60                                                            254             0.36                                                          255             1.3                                                           256             4.4                                                           258             3.1                                                           260             1                                                             261             63                                                            262             2                                                             263             46                                                            264             16                                                            265             0.52                                                          266             8.2                                                           267             0.68                                                          269             1.4                                                           270             10                                                            271             1.9                                                           272             23                                                            273             2                                                             274             2.3                                                           275             1.9                                                           276             3                                                             277             54                                                            278             10                                                            279             34                                                            280             58                                                            281             36                                                            282             22                                                            285             9.4                                                           ______________________________________                                    

It is apparant from Table 3 that the objected compound and salts thereofof the present invention have excellent substance P receptorantagonizing actitity.

EXAMPLES !

The present invention is hereinafter described in more detail by meansof the following reference examples and working examples. The followingReference Examples and Examples are further descriptive of the presentinvention. It should be understood that these are merely illustrativeand by no means definitive of the invention and that many changes andmodifications can be made within the scope of the invention.

Elution in column chromatography in the reference and working exampleswas conducted with observation by TLC (Thin Layer Chromatography),unless otherwise stated. In the TLC observations, a TLC plate of Merck60F₂₅₄ was used, in which the developing solvent was the same as thecolumn chromatography eluent and the detector was a UV detector. Silicagel used for column chromatography was Merck Silica gel 60 (70-230mesh). Room temperature is generally defined to be between about 10° C.and 35° C.

Extracts were dried over sodium sulfate or magnesium sulfate.

The abbreviations in the working and reference examples are defined asfollows:

DMF for dimethylformamide, THF for tetrahydrofuran, DMSO for dimethylsulfoxide, Hz for Herz, J for coupling constant, m for multiplet, q forquartet, t for triplet, d for doublet, s for singlet and b for broad.

EXAMPLE 16-Chloro-N-(2,4-difluorophenyl)-1-oxo-4-phenyl-1H-2-benzopyran-3-carboxamidMethod A

To a solution of 6-chloro-1-oxo-4-phenyl-1H-2-benzopyran-3-carboxylicacid (450 mg) in dichloromethane (20 ml) were added oxalyl chloride(0.22 ml) and DMF (one drop) at room temperature, followed by stirringfor 1 hour. After the solvent was distilled off, the residue wasdissolved in anhydrous THF (20 ml). To this solution was added asolution of 2,4-difluoroaniline (0.30 ml) and triethylamine (0.27 ml) inanhydrous THF, followed by stirring at room temperature for 1.5 hours.After the solvent was distilled off, ethyl acetate was added to theresidue, which was then washed successively with water, dilutehydrochloric acid, water, aqueous sodium hydrogen carbonate and waterand then dried, after which the solvent was distilled off, to yield thetitle compound as colorless crystals (520 mg).

Method B

To a solution of 6-chloro-1-oxo-4-phenyl-1H-2-benzopyran-3-carboxylicacid (300 mg) in 1,2-dichloroethane (10 ml) were added1-hydroxybenzotriazole (135 mg) and 1,3-dicyclohexylcarbodiimide (220mg), followed by stirring at room temperature for 0.5 hours. To thismixture was added 2,4-difluoroaniline (0.20 ml), followed by stirring atroom temperature for 16 hours. After the reaction mixture wasconcentrated, ethyl acetate was added to the residue, and theprecipitated crystals were separated by filtration. The filtrate waswashed successively with dilute hydrochloric acid, water, aqueouspotassium carbonate and water and then dried, after which the solventwas distilled off, to yield the title compound as colorless crystals(350 mg).

Melting point: 189°14 191° C. (recrystallized from ethyl acetate-ethylether) NMR (200 MHz, CDCl₃) ppm: 6.70-6.93 (2H,m), 7.08 (1H,d, J=2.2Hz), 7.24-7.63 (6H,m), 8.10 (1H,m), 8.39 (1H,d,J=8.6 Hz), 8.68 (1H,b)

Elemental analysis (for C₂₂ H₁₂ NO₃ ClF₂): Calculated (%): C, 64.17; H,2.94; N, 3.40 Found (%): C, 63.91; H, 2.84; N, 3.44

In the working examples 2 to 97 below, unless otherwise specified, thedesired compound was obtained in substantially the same method as MethodA or Method B in Example 1, using the carboxylic acid and anilinecorresponding thereto as starting materials. For the compounds ofrespective examples, the method of synthesis (Method A or Method B) isspecified with (A) or (B) after the name of the compound.

EXAMPLE 24-(4-Fluorophenyl)-6-methyl-1-oxo-N-(2,4,6-trimethoxyphenyl)-1H-2-benzopyran-3-carboxamide(A)

Melting point: 228°-229° C. (recrystallized from ethanol) NMR (200 MHz,CDCl₃) ppm: 2.39 (3H,s), 3.76 (6H,s), 3.77 (3H,s), 6.10 (2H,s), 6.88(1H,s), 7.10-7.30 (4H,m), 7.44 (1H,d,J=8.0 Hz), 7.90 (1H,s), 8.31(1H,d,J=8.0 Hz)

Elemental analysis (for C₂₆ H₂₂ NO₆ F): Calculated (%): C, 67.38; H,4.78; N, 3.02 Found (%): C, 67.21; H, 4.92; N, 3.13

EXAMPLE 3N-(2,4-Difluorophenyl)-4-(4-fluorophenyl)-6-(1-methylethyl)-2-oxo-2H-1-benzopyran-3-carboxamide(A)

Melting point: 175°-176° C. (recrystallized from ethyl acetate-isopropylether) NMR(200 MHz, CDCl₃) ppm: 1.17 (6H,d,J=7.0 Hz), 2.87 (1H,m),6.70-6.90 (2H,m), 6.96 (1H,d, J=2.0 Hz), 7.18-7.57 (6H,m), 8.12 (1H,m),9.74 (1H,b)

Elemental analysis (for C₂₅ H₁₈ NO₃ F₃): Calculated (%): C, 68.65; H,4.15; N, 3.20 Found (%): C, 68.68; H, 4.00; N, 3.14

EXAMPLE 4 N-2,6-Bis(1-methylethyl)phenyl!-4-(4-fluorophenyl)-6-(1-methylethyl)-2-oxo-2H-1-benzopyran-3-carboxamide(A)

Melting point: 220°-222° C. (recrystallized from ethyl acetate-hexane)NMR (200 MHz, CDCl₃) ppm: 1.11 (12H,d,J=6.8 Hz), 1.18 (6H,d,J=6.8 Hz),2.87 (1H,m), 2.97 (2H,m), 6.97 (1H,d, J=1.4 Hz), 7.10-7.55 (9H,m), 8.18(1H,b)

Elemental analysis (for C₃₁ H₃₂ NO₃ F): Calculated (%): C, 76.68; H,6.64; N, 2.88 Found (%): C, 76.30; H, 6.60; N, 2.84

EXAMPLE 5 N-2,6-Bis(1-methylethyl)phenyl!-4-(2-chlorophenyl)-6,7-dimethyl-2-(1-methylethyloxy)-3-quinolinecarboxamide(A)

Melting point: 176°-178° C. (recrystallized from ethyl ether-hexane) NMR(200 MHz, CDCl₃) ppm: 1.04 (12H,bs), 1.46 (3H,d,J=6.4 Hz), 1.51(3H,d,J=6.2 Hz), 2.26 (3H,s), 2.43 (3H,s), 2.60-3.80 (2H,bs), 5.78(1H,m), 6.82 (1H,s), 7.00-7.65 (8H,m), 7.67 (1H,s)

Elemental analysis (for C₃₃ H₃₇ N₂ O₂ Cl): Calculated (%): C, 74.91; H,7.05; N, 5.29 Found (%): C, 74.98; H, 7.09; N, 5.35

EXAMPLE 6 4- 3,5-Bis-(1,1-dimethylethyl)-4-hydroxyphenyl!-N-2,6-bis(1-methylethyl)phenyl!-1,2-dihydro-2-methyl-1-oxo-3-isoquinolinecarboxamide(A)

Melting point: 334°-338° C. (recrystallized from acetone-methanol) NMR(200 MHz, CDCl₃) ppm: 1.24 (12H,d,J=7.0 Hz), 1.64 (18H,s), 2.35 (1H,s),2.74 (1H,m), 3.97 (3H,s), 5.59 (1H,s), 7.09-7.13 (1H,m), 7.29-7.50(5H,m), 7.67-7.73 (2H,m), 8.66-8.71 (1H,m)

Elemental analysis (for C₃₇ H₄₆ N₂ O₃ •1/4H₂ O): Calculated (%): C,77.79; H, 8.20; N, 4.90 Found (%): C, 77.75; H, 8.22; N, 4.75

EXAMPLE 7 N-2,6-Bis(1-methylethyl)phenyl!-4-(2-chlorophenyl)-1-ethyl-6,7-dimethyl-2-oxo-3-quinolinecarboxamide(A)

Melting point: 217°-222° C. (recrystallized from acetone-hexane) NMR(200 MHz, CDCl₃)ppm: 1.11 (12H,d,J=6.2 Hz), 1.50 (3H,t,J=7.2 Hz), 2.19(3H,s), 2.44 (3H,s), 3.10 (2H,bs), 4.38-4.68 (2H,m), 6.79 (1H,s),7.02-7.50 (8H,m), 9.79 (1H,s)

Elemental analysis (for C₃₂ H₃₅ N₂ O₂ Cl): Calculated (%): C, 74.62; H,6.85; N, 5.44 Found (%): C, 74.70; H, 7.06; N, 5.41

EXAMPLE 8N-(2,5-Dimethoxyphenyl)-4-(4-fluorophenyl)-1-oxo-1H-2-benzopyran-3-carboxamide(A)

Melting point: 186°-187° C. (recrystallized from acetone-ethyl ether)NMR (200 MHz, CDCl₃) ppm: 3.72 (3H,s), 3.90 (3H,s), 6.59 (1H,dd,J=12.0,3.0 Hz), 6.81 (1H,d,J=8.8 Hz), 7.10-7.30 (5H,m), 7.60-7.72 (2H,m), 7.96(1H,d,J=2.8 Hz), 8.44 (1H,dd,J=7.2, 1.0 Hz), 9.23 (1H,b)

Elemental analysis (for C₂₄ H₁₈ O₅ F): Calculated (%): C, 68.73; H,4.33; N, 3.34 Found (%): C, 68.66; H, 4.37; N, 3.47

EXAMPLE 93,4-trans-4-(4-Fluorophenyl)-1,2,3,4-tetrahydro-2-methyl-N-(3-methylphenyl)-1-oxo-3-isoquinolinecarboxamide(A)

Melting point: 273°-275° C. (recrystallized from chloroform) NMR (200MHz, DMSO-d₆) ppm: 2.25 (3H,s), 2.88 (3H,s), 4.54 (1H,s), 4.65 (1H,s),6.83-7.43 (11H,m), 7.96-8.00 (1H,m)

Elemental analysis (for C₂₄ H₂₁ N₂ O₂ F): Calculated (%): C, 74.21; H,5.45; N, 7.21 Found (%): C, 73.75; H, 5.20; N, 7.32

EXAMPLE 103,4-trans-4-(2-Chlorophenyl)-N-(2,4-difluorophenyl)-1,2,3,4-tetrahydro-1,6,7-trimethyl-2-oxo-3-quinolinecarboxamide(A)

Melting point: 230°-233° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.19 (3H,s), 2.29 (3H,s), 3.44 (3H,s),4.00 (1H, d,J=1.6 Hz), 5.30 (1H,s like), 6.57-6.65 (1H,m), 6.72-6.90(2H,m), 6.89 (1H,s), 7.00-7.23 (2H,m), 7.01 (1H,s), 7.37-7.45 (1H,m),8.11-8.26 (1H,m), 8.43 (1H,bs)

Elemental analysis (for C₂₅ H₂₁ N₂ O₂ ClF₂): Calculated (%): C, 66.01;H, 4.65; N, 6.16 Found (%): C, 65.98; H, 4.85; N, 6.03

EXAMPLE 11 3,4-trans-N-2,6-Bis(1-methylethyl)phenyl!-6-chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinolinecarboxamide(A)

Melting point: 201°-203° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 0.98 (6H,d,J=6.2 Hz), 1.08 (6H,d,J=6.6Hz), 2.68 (2H,m), 3.45 (3H,s), 4.02 (1H,d,J=4.0 Hz), 4.49 (1H,d,J=3.6Hz), 6.90-7.50 (12H,m)

Elemental analysis (for C₂₉ H₃₁ N₂ O₂ Cl): Calculated (%): C, 73.33; H,6.58; N, 5.90 Found (%): C, 73.06; H, 6.61; N,.5.92

EXAMPLE 12 3,4-cis-4- 3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl!-N-2,6-bis(1-methylethyl)phenyl!-1,2,3,4-tetrahydro-2-methyl-1-oxo-3-isoquinolinecarboxamide

A mixture of the compound obtained in Example 6 (300 mg), acetic acid (8ml) and 10% palladium-carbon (50% hydrated) (150 mg) was stirred at 90°to 100° C. in a hydrogen atmosphere for 15 hours. After cooling, themixture was filtered, the filtrate being distilled to remove thesolvent. The residue was dissolved in ethyl acetate and washedsuccessively with water, aqueous sodium hydrogen carbonate and water andthen dried, after which the solvent was distilled off, to yield thetitle compound as colorless crystals (160 mg).

Melting point: 268°-270° C. (recrystallized from acetone-ethyl ether)NMR (200 MHz, CDCl₃) ppm: 0.87 (6H,d,J=6.8 Hz), 1.00 (6H,d,J=6.8 Hz),1.39 (18H,s), 2.41 (1H,m), 3.41 (3H,s), 4.40 (1H,d,J=5.6 Hz), 4.93(1H,d, J=5.6 Hz), 5.22 (1H,s), 6.82 (1H,s), 7.02-7.53 (8H,m), 8.16-8.20(1H,m)

Elemental analysis (for C₃₇ H₄₈ N₂ O₃): Calculated (%): C, 78.13; H,8.51; N, 4.92 Found (%): C, 77.94; H, 8.60; N, 4.83

EXAMPLE 13 3,4-trans-N-2,6-Bis(1-methylethyl)phenyl!-4-(4-fluorophenyl)-3,4-dihydro-6-(1-methylethyl)-2-oxo-2H-1-benzopyran-3-carboxamide

The compound obtained in Example 4 was reacted in substantially the samemanner as in Example 12 to yield the title compound as colorlesscrystals.

Melting point: 223°-225° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 0.98, 1.06 (each 6H,d,J=7.0 Hz), 1.16,1.17 (each 3H,d,J=7.0 Hz), 2.65 (2H,b), 2.82 (1H,m), 3.98 (1H,d,J=7.0Hz), 5.00 (1H,d,J=7.0 Hz), 6.86-7.29 (10H,m)

Elemental analysis (for C₃₁ H₃₄ NO₃ F): Calculated (%): C, 76.36; H,7.03; N, 2.87 Found (%): C, 76.06; H, 7.14; N, 3.08

EXAMPLE 14N-(2,5-Dimethoxyphenyl)-4-(4-fluorophenyl)-3,4-dihydro-1-oxo-1H-2-benzopyran-3-carboxamide

The compound obtained in Example 8 was reacted in substantially the samemanner as in Example 12 to yield the title compound as colorlesscrystals.

Melting point: 133°-136° C. (recrystallized from acetone-ethyl ether)NMR (200 MHz, CDCl₃) ppm: 3.72 (3H,s), 3.78 (3H,s), 4.83 (1H,d,J=3.5Hz), 5.35 (1H,d,J=3.5 Hz), 6.57 (1H,dd,J=12.0, 2.8 Hz), 6.73 (1H,d,J=9.0Hz), 6.83-7.07 (4H,m), 7.31 (1H,d,J=7.2 Hz), 7.50-7.70(2H,m), 7.86 (1H,d, J=2.6 Hz), 8.25 (1H,d,J=7.6 Hz), 8.49 (1H,b)

Elemental analysis (for C₂₄ H₂₀ NO₅ F•1/3H₂ O): Calculated (%): C,67.94; H, 4.91; N, 3.30 Found (%): C, 67.73; H, 4.98; N, 3.30

EXAMPLE 15 3,4-trans-N-2,6-Bis(1-methylethyl)phenyl!-4-(2-chlorophenyl)-1,2,3,4-tetrahydro-1,6,7-trimethyl-3-quinolinecarboxamide(A)

Melting point: 145°-146° C. (recrystallized from ethyl ether-hexane) NMR(200 MHz, CDCl₃) ppm: 1.06 (12H,d like, J=6.6 Hz), 2.07 (3H,s), 2.24(3H,s), 2.71 (2H,m), 3.01 (3H,s), 3.11 (1H,m), 3.25-3.52 (2H,m), 4.90(1H,d, J=3.2 Hz), 6.62 (2H,s), 6.80-6.90 (1H,m), 7.05-7.30 (5H,m),7.40-7.50 (1H,m), 7.56 (1H,bs)

Elemental analysis (for C₃₁ H₃₇ N₂ OCl): Calculated (%): C, 76.13; H,7.62; N, 5.73 Found (%): C, 75.95; H, 7.74; N, 5.80

EXAMPLE 16 N-2,6-Bis(1-methylethyl)phenyl!-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinolineacetamide(trans:cis=about 3:1 mixture) (A)

Melting point: 214°-216° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 0.90-1.30, 1.17 (total 12H,m,d,J=7.0Hz), 2.06, 2.35-3.05 (total 2H,d,J=5.8 Hz, m), 2.90-3.20 (2H,m),3.35-3.70 (1H,m), 3.38, 3.46, 3.51 (total 3H, each s), 4.30, 4.33, 4.41(1H, each d,J=6.2 Hz, J=11.0 Hz, J=8.0 Hz), 6.55-7.60 (13H,m)

Elemental analysis (for C₃₀ H₃₄ N₂ O₂): Calculated (%): C, 79.26; H,7.54; N, 6.16 Found (%): C, 79.10; H, 7.65; N, 6.30

EXAMPLE 174-(2-Chlorophenyl)-1,2,3,4-tetrahydro-1-methyl-N-(3-methylphenyl)-2-oxo-3-quinolineacetamide(trans:cis=about 3:1 mixture) (A)

Melting point: 161°-162° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.25-2.55 (1H,m), 2.31 (3H,s),2.60-2.80 (1H,m), 3.40-3.65 (0.75H,m), 3.47 (2.25H,s), 3.50 (0.75H,s),3.70-3.85 (0.25H,m), 4.76 (0.75H,d,J=13 Hz), 5.05 (0.25H,d,J=7.0 Hz),6.63 (0.75H,d,J=7.8 Hz), 6.85-7.50 (11.25H,m), 7.85 (0.25H,bs), 8.11(0.75H,bs)

Elemental analysis (for C₂₅ H₂₃ N₂ O₂ Cl•0.2H₂ O): Calculated (%): C,71.07; H, 5.58; N, 6.63 Found (%): C, 71.07; H, 5.56; N, 6.53

EXAMPLE 18 N-2,6-Bis(1-methylethyl)phenyl!-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methyl-2-oxo-4-phenyl-3-quinolineacetamide(trans:cis=about 4:1 mixture) (A)

Melting point: 205°-207° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 0.85-1.35, 1.17 (total 12H,m,d, J=6.8Hz), 2.04, 2.55-2.80 (total 2H,d,J=5.2 Hz, m), 3.06 (2H,m), 3.30-3.55(1H,m), 3.36, 3.42, 3.45 (total 3H, each s), 3.62, 3.65 (total 3H, eachs), 3.89, 3.90, 3.94 (total 3H, each s), 4.24, 4.33 (total 1H, each d,J=10 Hz, J=11Hz), 6.21, 6.30 (total 1H, each s), 6.56, 6.66 (total 1H,each s), 7.00-7.50 (9H,m)

Elemental analysis (for C₃₂ H₃₈ N₂ O₄): Calculated (%): C, 74.68; H,7.44; N, 5.44 Found (%): C, 74.82; H, 7.50; N, 5.86

EXAMPLE 19 N-2,6-Bis-(1-methylethyl)phenyl!-6-chloro-1,2,3,4-tetrahydro-1,4-dimethyl-2-oxo-4-phenyl-3-quinolineacetamide(A)

Melting point: 236°-237° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.13 (12H,d,J=6.6 Hz), 1.49 (3H,s),2.01 (1H, dd,J=14.4 Hz, J=2.0 Hz), 2.88 (1H,dd,J=14.4 Hz, J=9.6 Hz),3.00 (2H,m), 3.40, 3.45 (total 3H, each s), 3.86 (1H,d,J=9.8 Hz), 6.53(1H,d,J=2.4 Hz), 6.9-7.5 (10H,m)

Elemental analysis (for C₃₁ H₃₅ N₂ O₂ Cl): Calculated (%): C, 74.01; H,7.01; N, 5.57 Found (%): C, 73.71; H, 6.89; N, 5.87

EXAMPLE 20 3,4-trans-N-2,6-Bis(1-methylethyl)phenyl!-4-(2-chlorophenyl)-1,2,3,4-tetrahydro-1,6,7-trimethyl-2-oxo-3-quinolineacetamide(A)

Melting point: 213°-215° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 0.95-1.30, 1.16 (total 12H,m,d,J=6.8Hz), 2.06, 2.13 (total 3H, each s), 2.24, 2.30 (total 3H, each s), 2.56(1H,dd,J=15.0, 3.8 Hz), 2.79 (1H,dd,J=15.0, 7.8 Hz), 3.06 (2H,m), 3.39,3.45 (total 3H, each s), 3.40-3.60 (1H,m), 4.69, 4.85 (total 1H, each d,J=10.0 Hz, J=13.0 Hz), 6.23, 6.47 (total 1H, each s), 6.79, 6.90 (total1H, each s), 7.00-7.30, 7.40-7.55, 7.55 (total 8H,m,m,s)

Elemental analysis (for C₃₂ H₃₇ N₂ O₂ Cl): Calculated (%): C, 74.33; H,7.21; N, 5.42 Found (%): C, 74.13; H, 7.09; N, 5.83

EXAMPLE 21 3,4-trans-N-2,6-Bis(1-methylethyl)phenyl!-6-chloro-4-(2-chlorophenyl)-1,2,3,4-tetrahydro-1-methyl-2-oxo-3-quinolineacetamide(A)

Melting point: 231°-234° C. (recrystallized from ethyl acetate-isopropylether-ethanol) NMR (200 MHz, CDCl₃) ppm: 1.00-1.30, 1.16 (total12H,m,d,J=6.8 Hz), 2.55 (1H,dd,J=15.0, 4.0 Hz), 2.76 (1H,dd,J=15.0, 7.4Hz), 3.06 (2H,m), 3.39, 3.45 (total 3H, each s), 3.40-3.70 (1H,m), 4.83,4.96 (total 1H, each d, J=12.0 Hz, J=14.0 Hz), 6.46, 6.62 (total 1H,each s), 6.90-7.56 (10H,m)

Elemental analysis (for C₃₀ H₃₂ N₂ O₂ Cl₂ •0.2CH₃ CO₂ C₂ H₅): Calculated(%): C, 68.37; H, 6.26; N, 5.18 Found (%): C, 68.14; H, 6.42; N, 5.24

EXAMPLE 22 3,4-cis-6-Chloro-1,2,3,4- tetrahydro -1-methyl-N-2-methyl-6-(1-methylethyl)phenyl!-2-oxo-4-phenyl-3-quinolineacetamide

To a solution of6-chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinolineaceticacid (trans:cis=about 4:1 mixture, described in Reference Example 12)(220 mg) in anhydrous THF (7 ml) were added oxalyl chloride (0.11 ml)and DMF (one drop) at room temperature, followed by stirring for 0.5hours. After the solvent was distilled off, the residue was dissolved inanhydrous THF (10 ml). To this solution was added a solution of2-isopropyl-6-methylaniline (0.135 ml) and triethylamine (0.11 ml) inanhydrous THF (5 ml), followed by stirring at room temperature for 0.5hours. After the solvent was distilled off, ethyl acetate was added tothe residue, which was then washed successively with water, dilutehydrochloric acid, water, aqueous sodium hydrogen carbonate and waterand then dried, followed by concentration, to yield the compound ofExample 23 as colorless crystals (120 mg). After the filtrate wasdistilled to remove the solvent, the residue was subjected to silica gelcolumn chromatography (eluted with hexane:ethyl acetate=1:0→3:1); thetitle compound, as colorless crystals (35 mg), was obtained in the firstfraction, the compound of Example 23 described below, as additionalcolorless crystals (25 mg), was obtained in the second fraction.

Melting point: 162°-164° C. (recrystallized from isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 1.17 (3H,d,J=7.2 Hz), 1.20 (3H,d,J=7.2 Hz), 2.23(3H,s), 2.37 (1H,dd,J=15.1, 4.8 Hz), 2.91 (1H,dd,J=15.1, 7.8 Hz), 3.09(1H,m),3.48(3H,s),3.65(1H,m),4.25(1H,d,J=6.7Hz),7.01-7.37(11H,m)

Elemental analysis (for C₂₈ H₂₉ N₂ O₂ Cl): Calculated (%): C, 72.95; H,6.34; N, 6.08 Found (%): C, 72.64; H, 6.57; N, 6.19

EXAMPLE 23 3,4-trans-6-Chloro-1-methyl-N-2-methyl-6-(1-methylethyl)phenyl!-2-oxo-4-phenyl-1,2,3,4-tetrahydro-3-quinolineacetamide

The title compound, along with the compound of Example 22, was obtainedas colorless crystals by the method described in Example 22.

Melting point: 238°-240° C. (recrystallized from ethyl acetate-ethylether) NMR (200 MHz, CDCl₃ +DMSO-d₆) ppm: 1.16 (3H,d,J=7.0 Hz), 1.17(3H, d,J=7.0 Hz), 2.21 (3H,s), 2.57-2.64 (2H,m), 3.10 (1H,m), 3.39(3H,s), 3.34-3.50 (1H,m), 4.35 (1H,d, J=8.8 Hz), 6.79 (1H,d,J=2.4 Hz),7.01-7.40 (10H, m), 8.48 (1H,s)

Elemental analysis (for C₂₈ H₂₉ N₂ O₂ Cl): Calculated (%): C, 72.95; H,6.34; N, 6.08 Found (%): C, 72.64; H, 6.40; N, 6.15

The compounds of Examples 24 through 33 were obtained in the samereaction as in Example 22, using the carboxylic acid used in Example 22and respective corresponding anilines.

EXAMPLE 243,4-cis-6-Chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-N-(2,4,6-trimethoxyphenyl)-3-quinolineacetamide

Melting point: 160°-162° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.20 (1H,dd,J=14.4 Hz, J=2.0 Hz), 3.10(1H, dd,J=14.4 Hz, J=9.6 Hz), 3.39, 3.46 (total 3H, each s), 3.81(3H,s), 3.84 (6H, s), 4.34 (1H,d,J=7.0 Hz), 6.17 (2H,s), 6.65 (1H, s),6.9-7.3 (7H,m)

Elemental analysis (for C₂₇ H₂₇ N₂ O₅ Cl): Calculated (%): C, 65.52; H,5.50; N, 5.66 Found (%): C, 65.51; H, 5.84; N, 5.84

EXAMPLE 253,4-trans-6-Chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-N-(2,4,6-trimethoxyphenyI)-3-quinolineacetamide

Melting point: 157°-158° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.58 (1H,d,J=6.2 Hz), 3.32, 3.40 (total3H, each s), 3.66, 3.79 (total 9H, each s), 4.37 (1H,d,J=7.6 Hz), 6.14(2H,s), 6.85 (1H,d,J=2.4 Hz), 6.7-7.4 (7H,m)

Elemental analysis (for C₂₇ H₂₇ N₂ O₅ Cl): Calculated (%): C, 65.52; H,5.50; N, 5.66 Found (%): C, 65.47; H, 5.60; N, 5.74

EXAMPLE 263,4-cis-6-Chloro-N-(2,4-difluorophenyl)-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinolineacetamide

Melting point: 198°-200° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.34 (1H,dd,J=15.0 Hz, J=4.8 Hz), 2.81(1H, dd,J=15.0 Hz, J=4.0 Hz), 3.47 (3H,s), 3.61 (1H,m), 4.19 (1H,d,J=6.6Hz), 6.8-7.3 (9H,m), 7.96 (1H,bs), 8.21 (1H,m)

Elemental analysis (for C₂₄ H₁₉ N₂ O₂ ClF₂): Calculated (%): C, 65.38;H, 4.34; N, 6.35 Found (%): C, 65.32; H, 4.41; N, 6.37

EXAMPLE 273,4-trans-6-Chloro-N-(2,4-difluorophenyl)-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinolineacetamide

Melting point: 165°-168° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.55 (1H,m), 3.43 (3H,s), 3.43 (1H,m),4.18 (1H,d,J=13.2 Hz), 6.60 (1H,m), 6.86 (2H,m), 6.97 (1H,d,J=8.6 Hz),7.2-7.5 (7H,m), 7.8 (1H,bs), 8.2 (1H,m)

Elemental analysis (for C₂₄ H₁₉ N₂ O₂ ClF2): Calculated (%): C, 65.38;H, 4.34; N, 6.35 Found (%): C, 65.51; H, 4.34; N, 6.36

EXAMPLE 283,4-cis-6-Chloro-N-(2,6-dimethylphenyl)-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinolineacetamide

Melting point: 203°-205° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.30 (6H,s), 2.37 (1H,dd,J=15.2 Hz,J=4.8 Hz), 2.87 (1H,dd,J=15.0 Hz, J=8.2 Hz), 3.47 (3H,s), 3.64 (1H,m),4.24 (1H, d,J=6.6 Hz), 7.0-7.4 (1H,m)

Elemental analysis (for C₂₆ H₂₅ N₂ O₂ Cl): Calculated (%): C, 72.13; H,5.82; N, 6.47 Found (%): C, 71.75; H, 5.84; N, 6.55

EXAMPLE 293,4-trans-6-Chloro-N-(2,6-dimethylphenyl)-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinolineacetamide

Melting point: 201°-203° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.20 (6H,s), 2.59 (2H,m), 3.38 (1H,m),3.43 (3H,s), 4.29 (1H,d,J=12.0 Hz), 6.64 (1H,m), 6.9-7.4 (10H,m)

Elemental analysis (for C₂₆ H₂₅ N₂ O₂ Cl): Calculated (%): C, 72.13; H,5.82; N, 6.47 Found (%): C, 71.57; H, 5.76; N, 6.65

EXAMPLE 303,4-cis-6-Chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-N-(2,4,6-trimethylphenyl)-3-quinolineacetamide

Melting point: 224°-227° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.19 (6H,s), 2.25 (3H,s), 2.35(1H,dd,J=15.2 Hz,J=4.8 Hz), 2.86 (1H,dd,J=15.4 Hz, J=7.8 Hz), 3.47(3H,s), 3.63 (1H,m), 4.24 (1H,d,J=6.6 Hz), 6.88 (1H,s), 7.0-7.3 (9H,m)

Elemental analysis (for C₂₇ H₂₇ N₂ O₂ Cl): Calculated (%): C, 72.55; H,6.09; N, 6.27 Found (%): C, 72.33; H, 6.27; N, 6.44

EXAMPLE 313,4-trans-6-Chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-N-(2,4,6-trimethylphenyl)-3-quinolineacetamide

Melting point: 191°-193° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.16 (6H,s), 2.24 (3H,s), 2.58 (2H,m),3.4 (1H,m), 3.42 (3H,s), 4.29 (1H,d,J=11.8 Hz), 6.65 (1H,m), 6.86(2H,s), 6.98 (1H,d, J=8.6 Hz), 7.1-7.5 (6H,m)

Elemental analysis (for C₂₇ H₂₇ N₂ O₂ Cl): Calculated (%): C, 72.55; H,6.09; N, 6.27 Found (%): C, 72.64; H, 6.11; N, 6.36

EXAMPLE 32 3,4-cis-N-2,6-Bis(1-methylethyl)phenyI!-6-chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinolineacetamide

Melting point: 208°-210° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.18 (12H, t like, J=6.8 Hz), 2.37 (1H,dd, J=15.0, 5.4 Hz), 2.96 (1H,dd,J=15.0, 7.6 Hz), 3.08 (2H,m), 3.48(3H,s), 3.55-3.70 (1H,m), 4.27 (1H,d,J=6.6 Hz), 7.00-7.35 (12H,m)

Elemental analysis (for C₃₀ H₃₃ N₂ O₂ Cl): Calculated (%): C, 73.68; H,6.80; N, 5.73 Found (%): C, 73.75; H, 6.86; N, 5.68

EXAMPLE 33 3,4-trans-N-2,6-Bis(1-methylethyl)phenyl!-6-chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinolineacetamide

Melting point: 259°-260° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, DMSO-d₆) ppm: 1.11 (12H,d,J=7.0 Hz), 1.83 (1H,dd,J=15.0, 9.0 Hz), 2.37 (1H,dd,J=15.0, 5.2 Hz), 2.67 (1H,m), 2.90-3.20(2H,m), 2.96 (3H,s), 3.32 (3H,s), 4.19 (1H,d,J=4.8 Hz), 6.68-6.82(2H,m), 7.00-7.40 (9H,m), 9.17 (1H,s)

Elemental analysis (for C₃₀ H₃₃ N₂ O₂ Cl): Calculated (%): C, 73.68; H,6.80; N, 5.73 Found (%): C, 73.72; H, 6.92; N, 5.63

EXAMPLE 34 3,4-cis-N-2,6-Bis-(1-methylethyl)phenyl!-6-chloro-3,4-dihydro-2-oxo-4-phenyl-2H-1-benzopyran-3-acetamide(A)

Melting point: 229°-232° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.18 (12H,d,J=7.0 Hz), 2.42(1H,dd,J=15.8 Hz, J=6.2 Hz), 2.85 (1H,dd,J=16.0 Hz, J=7.0 Hz), 3.08(2H,m), 3.84 (1H,m), 4.39 (1H,d,J=7.0 Hz), 6.5 (1H,bs)7.1-7.4 (10H,m)

Elemental analysis (for C₂₉ H₃₀ NO₃ Cl): Calculated (%): C, 73.17; H,6.35; N, 2.94 Found (%): C, 73.06; H, 6.48; N, 2.97

EXAMPLE 35 3,4-trans-N-2,6-Bis-(1-methylethyl)phenyl!-3,4-dihydro-6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-acetamide(A)

Melting point: 245°-247° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.17 (12H,d,J=6.8 Hz), 2.17, 2.21(total 3H, each s), 2.63 (1H,m), 3.06 (2H,m), 3.58 (2H,m), 4.44(1H,d,J=11.2 Hz), 6.49 (1H,bs), 6.78 (1H,bs), 7.0-7.5 (6H,m)

Elemental analysis (for C₃₀ H₃₃ NO₃): Calculated (%): C, 79.09; H, 7.30;N, 3.07 Found (%): C, 79.06; H, 7.39; N, 3.07

EXAMPLE 36 3,4-cis-N-2,6-Bis(1-methylethyl)phenyl!-6-chloro-1,2,3,4-tetrahydro-1-methyl-4-phenyl-3-quinolineacetsmide(B)

Melting point: 239°-241° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, DMSO-d₆)ppm: 1.11 (12H,d,J=6.6 Hz), 2.25-2.35(2H,m), 3.02 (2H,m), 3.20-3.40 (3H,m), 3.32 (3H,s), 4.30 (1H,d,J=6.6Hz), 6.88 (1H, d,J=2.2 Hz), 7.00-7.50 (10H,m), 9.20 (1H,s)

Elemental analysis (for C₃₀ H₃₅ N₂ OCl): Calculated (%): C, 75.85; H,7.43; N, 5.90 Found (%): C, 76.17; H, 7.52; N, 5.77

EXAMPLE 373,4-cis-6-Chloro-1,2,3,4-tetrahydro-1-methyl-4-phenyl-N-(2,4,6-trimethoxyphenyl)-3-quinolineacetamide(B)

Melting point: 179°-180° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.96 (1H,dd,J=15, 8.2 Hz), 2.21 (1H,dd,J=15, 6.2 Hz), 2.86 (1H,m), 2.99 (3H,s), 3.15-3.30 (2H,m), 3.81 (9H,s),4.21 (1H,d,J=4.6 Hz), 6.15 (2H,s), 6.34 (1H,s), 6.58 (1H,d,J=8.8 Hz),6.84 (1H,s like), 7.00-7.35 (6H,m)

Elemental analysis (for C₂₇ H₂₉ N₂ O₄ Cl): Calculated (%): C, 67.42; H,6.08; N, 5.82 Found (%): C, 67.36; H, 6.20; N, 5.67

EXAMPLE 383,4-cis-6-Chloro-N-(2,4-difluorophenyl)-1,2,3,4-tetrahydro-1-methyl-4-phenyl-3-quinolineacetamide(B)

Melting point: 161°-162° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.99 (1H,dd,J=15, 8.2 Hz), 2.24 (1H,dd,J=15, 6.4 Hz), 2.88 (1H,m), 2.97 (3H,s), 3.15-3.25 (2H,m), 4.21 (1H,d,J=4.8 Hz), 6.61 (1H,d,J=8.8 Hz), 6.80-7.35 (10H,m), 8.15-8.30 (1H,m)

Elemental analysis (for C₂₄ H₂₁ N₂ OClF₂ •0.2CH₃ CO₂ C₂ H₅): Calculated(%): C, 67.01; H, 5.12; N, 6.30 Found (%): C, 66.71; H, 4.96; N, 6.61

EXAMPLE 39 3,4-trans-N-2,6-Bis(1-methylethyl)phenyl!-1,2,3,4-tetrahydro-1-oxo-4-phenyl-2,6,7-trimethyl-3-isoquinolineacetamide(A)

Melting point: 280°-282° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.00-1.35, 1.23 (total 12H,m,d,J=7.0Hz), 2.22, 2.24, 2.28, 2.33 (total 6H, each s), 2.58 (1H,dd,J=15.0, 10.0Hz), 2.75, 2.96 (total 3H, each s), 2.89 (1H,dd, J=15.0, 4.6 Hz), 3.08(2H,m), 4.05-4.35 (1H,m), 4.21, 4.23 (total 1H, each s), 6.85-7.40(10H,m), 7.76, 7.94 (total 1H, each s)

Elemental analysis (for C₃₂ H₃₈ N₂ O₂): Calculated (%): C, 79.63; H,7.94; N, 5.80 Found (%): C, 79.56; H, 8.03; N, 5.74

EXAMPLE 403,4-trans-1,2,3,4-Tetrahydro-1-oxo-4-phenyl-N-(2,4,6-trimethoxyphenyl)-2,6,7-trimethyl-3-isoquinolineacetamide(A)

Melting point: 213°-214° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.23, 2.27, 2.34 (total 6H, each s),2.50 (1H,dd, J=14.0, 10.0 Hz), 2.78 (1H,dd,J=14.0, 4.8 Hz), 2.79, 2.98(total 3H, each s), 3.67, 3.82 (total 9H, each s), 3.90-4.30 (1H,m),4.23, 4.33 (total 1H,s,),6.02, 6.17 (total 2H, each s), 6.32, 6.41(total 1H, each s), 6.85-7.30 (6H,m), 7.80, 7.96 (total 1H, each s)

Elemental analysis (for C₂₉ H₃₂ N₂ O₅): Calculated (%): C, 71.29; H,6.60; N, 5.73 Found (%): C, 71.19; H, 6.62; N, 5.68

EXAMPLE 413,4-trans-N-(2,4-Difluorophenyl)-1,2,3,4-tetrahydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolineacetamide(A)

Melting point: 176°-177° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.26 (3H,s), 2.32 (3H,s), 2.61(1H,dd,J=15.0, 8.8 Hz), 2.77 (1H,dd,J=15.0, 5.0 Hz), 2.94 (3H,s),4.15-4.30 (1H,m), 4.17 (1H,s), 6.80-7.30 (8H,m), 7.41 (1H,bs), 7.92(1H,s), 8.10-8.30 (1H,m)

Elemental analysis (for C₂₆ H₂₄ N₂ O₂ F₂): Calculated (%): C, 71.87; H,5.57; N, 6.45 Found (%): C, 71.63; H, 5.68; N, 6.24

EXAMPLE 42 N-2,6-Bis(1-methylethyl)phenyl!-6-chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinoxalineacetamide(A)

Melting point: 205°-206° C. (recrystallized from ethyl ether-hexane) NMR(200 MHz, CDCl₃) ppm: 1.09 (6H,d,J=6.8 Hz), 1.16 (6H,d,J=7.0 Hz), 2.63(1H,dd,J=15.0, 8.6 Hz), 2.84 (1H,dd,J=15.0, 4.6 Hz), 3.02 (2H,m), 3.44(3H,s), 5.15 (1H,dd,J=8.6, 4.6 Hz), 6.90-7.35 (12H,m)

Elemental analysis (for C₂₉ H₃₂ N₃ O₂ Cl): Calculated (%): C, 71.08; H,6.58; N, 8.57 Found (%): C, 71.29; H, 6.61; N, 8.81

EXAMPLE 436-Chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-N-(2,4,6-trimethoxyphenyl)-3-quinoxalineacetamide(A)

Melting point: 236°-238° C. (recrystallized from THF-isopropyl ether)NMR (200 MHz, CDCl₃) ppm: 2.51 (1H,dd,J=14.0, 9.6 Hz), 2.73 (1H,dd,J=14.0, 3.8 Hz), 3.43 (3H, s), 3.65 (6H,s), 3.79 (3H,s), 5.10(1H,dd,J=9.6, 3.8 Hz), 6.11 (2H,s), 6.57 (1H,s), 6.90-7.35 (8H,m)

Elemental analysis (for C₂₆ H₂₆ N₃ O₅ Cl): Calculated (%): C, 62.97; H,5.28; N, 8.47 Found (%): C, 62.61; H, 5.48; N, 8.20

EXAMPLE 446-Chloro-N-(2,4-difiuorophenyl)-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinoxalineacetamide(A)

Melting point: 160°-161° C. (recrystallized from ethyl ether-hexane) NMR(200 MHz, CDCl₃) ppm: 2.68 (1H,dd,J=15.0, 7.0 Hz), 2.80 (1H,dd, J=15.0,5.8 Hz), 3.45 (3H,s), 4.99 (1H,t like, J=6.3 Hz), 6.78-7.42 (10H,m),7.76 (1H,m), 8.10-8.30 (1H,m)

Elemental analysis (for C₂₃ H₁₈ N₃ O₂ ClF₂): Calculated (%): C, 62.52;H, 4.11; N, 9.51 Found (%): C, 62.57; H, 4.23; N, 9.74

EXAMPLE 45 N-2,6-Bis(1-methylethyl)phenyl!-6-chloro-1,2-dihydro-1-methyl-2-oxo-4-phenyl-3-quinolineacetamide

To a solution of the compound obtained in Reference Example 18 (100 ml)in 1,2-dichloroethane (5 ml) were added 1-hydroxybenzotriazole (45 mg)and 1,3-dicyclohexylcarbodiimide (90 mg), followed by stirring at roomtemperature for 0.5 hours. To this mixture was added2,6-diisopropylaniline (0.5 ml), followed by heating under reflux for 10hours. After the reaction mixture was concentrated, ethyl acetate wasadded to the residue, the precipitated crystals were separated byfiltration. The filtrate was washed successively with hydrochloric acid,water, aqueous potassium carbonate and water and then dried, after whichthe solvent was distilled off, to yield the title compound as colorlesscrystals (105 mg).

Melting point: 237°-238° C. (recrystallized from acetone-ethyl ether)NMR (200 MHz, CDCl₃) ppm: 1.09 (12H,d,J=6.8 Hz), 2.98 (1H,m), 3.62(2H,s), 3.88 (3H,s), 7.09-7.60 (11H,m), 8.53 (1H,s)

Elemental analysis (for C₃₀ H₃₁ N₂ O₂ Cl): Calculated (%): C, 73.98; H,6.42; N, 5.75 Found (%): C, 73.75; H, 6.64; N, 5.72

EXAMPLE 466-Chloro-N-(2,4-difluorophenyl)-1,2-dihydro-1-methyl-2-oxo-4-phenyl-3-quinolineacetamide(B)

Melting point: 217°-218° C. (recrystallized from acetone-ethyl ether)NMR (200 MHz, CDCl₃) ppm: 3.54 (2H,s), 3.87 (3H,s), 6.77-6.87 (2H,m),7.15 (1H,d,J=2.4 Hz), 7.29-7.58 (9H,m), 8.19 (1H,m), 9.28 (1H,b)

Elemental analysis (for C₂₄ H₁₇ N₂ O₂ ClF₂): Calculated (%): C, 65.68;H, 3.90; N, 6.38 Found (%): C, 65.81; H, 4.16; N, 6.44

EXAMPLE 47 N-2,6-Bis(1-methylethyl)phenyl!-1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolineacetamide(A)

Melting point: 265°-270° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.00-1.30, 1.12 (total 12H,m,d,J=6.8Hz), 2.18, 2.24 (total 3H, each s), 2.34, 2.38 (total 3H, each s), 2.83(2H,m), 3.03, 3.14 (total 2H, each s), 3.77, 3.78 (total 3H, each s),6.55-6.80 (2H,m), 7.10-7.60 (8H,m), 8.15-8.30 (1H,m)

Elemental analysis (for C₃₂ H₃₆ N₂ O₂ •0.25CH₃ CO₂ C₂ H₅): Calculated(%): C, 78.85; H, 7.62; N, 5.57 Found (%): C, 78.82; H, 7.37; N, 5.56

EXAMPLE 48 N-2,6-Bis(1-methylethyl)phenyl!-6-chloro-1-oxo-4-phenyI-1H-2-benzopyran-3-acetamide(B)

Melting point: 183°-184° C. (recrystallized from ethyl acetate-ethylether) NMR (200 MHz, CDCl₃) ppm: 1.16 (12, d,J=6.8 Hz), 3.03 (2H,m),3.54 (2H,s), 6.94-7.55 (11H,m), 8.31 (1H,d,J=8.6 Hz)

Elemental analysis (for C₂₉ H₂₈ NO₃ Cl): Calculated (%): C, 73.49; H,5.95; N, 2.96 Found (%): C, 73.37; H, 6.15; N, 2.89

EXAMPLE 496-Chloro-N-(2,4-difluorophenyl)-1-oxo-4-phenyl-1H-2-benzopyran-3-acetamide(B)

Melting point: 244°-245° C. (recrystallized from ethyl acetate-ethylether) NMR (200 MHz, CDCl₃) ppm: 3.50 (2H,s), 6.81-6.90 (2H,m), 7.01(1H,d, J=1.6 Hz), 7.34-7.54 (6H,m), 8.25 (1H,m), 8.28 (1H,d,J=8.4 Hz)

Elemental analysis (for C₂₃ H₁₄ NO₃ ClF₂): Calculated (%): C, 64.88; H,3.31; N, 3.29 Found (%): C, 64.82; H, 3.49; N, 3.26

EXAMPLE 50 N-2,6-Bis(1-methylethyl)phenyl!-6-chloro-2-oxo-4-phenyl-2H-1-benzopyran-3-acetamide(A)

Melting point: 252°-255° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.15 (12H,d,J=7.0 Hz), 3.03 (2H,m),3.52 (2H,s), 7.0-7.6 (11H,m)

Elemental analysis (for C₂₉ H₂₈ NO₃ Cl): Calculated (%): C, 73.49; H,5.95; N, 2.96 Found (%): C, 73.36; H, 5.85; N, 3.26

EXAMPLE 516-Chloro-2-oxo-4-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-1-benzopyran-3-acetamide(A)

Melting point: 257°-259° C. (recrystallized from chloroform-ethylacetate-isopropyl ether) NMR (200 MHz, CDCl₃) ppm: 3.49 (2H,s), 3.79(9H,s), 6.12 (2H,s), 7.0-7.6 (9H,m)

Elemental analysis (for C₂₆ H₂₂ NO₆ Cl): Calculated (%): C, 65.07; H,4.62; N, 2.92 Found (%): C, 64.81; H, 4.44; N, 3.02

EXAMPLE 526-Chloro-N-(2,4-difiuorophenyl)-2-oxo-4-phenyl-2H-1-benzopyran-3-acetamide(A)

Melting point: 225°-227° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 3.49 (2H,s), 6.8-6.9 (2H,m), 7.05(1H,d, J=2.4 Hz), 7.3-7.6 (6H,m), 8.1-8.3 (2H,m)

Elemental analysis (for C₂₃ H₁₄ NO₃ ClF₂): Calculated (%): C, 64.88; H,3.31; N, 3.29 Found (%): C, 64.26; H, 3.54; N, 3.00

EXAMPLE 53 N-2,6-Bis(1-methylethyl)phenyl!-6-methyl-2-oxo-4-phenyl-2H-1-35-benzopyran-3-acetamide(A)

Melting point: 257°-258° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.14 (12H,d,J=7.0 Hz), 2.29 (3H,s),2.03 (2H,m), 3.51 (2H,s), 6.85 (1H,s), 7.1-7.7 (10H,m)

Elemental analysis (for C₃₀ H₃₁ NO₃): Calculated (%): C, 79.44; H, 6.89;N, 3.09 Found (%): C, 79.15; H, 6.75; N, 3.14

EXAMPLE 546-Methyl-2-oxo-4-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-1-benzopyran-3-acetamide(A)

Melting point: 256°-257° C. (recrystallized from chloroform-ethylacetate-isopropyl ether) NMR (200 MHz, CDCl₃) ppm: 2.27 (3H,s), 3.47(2H,s), 3.76 (3H,s), 3.78 (6H,s), 6.11 (2H,s), 6.83 (1H,s), 7.2-7.6(7H,m)

Elemental analysis (for C₂₇ H₂₅ NO₆): Calculated (%): C, 70.58; H, 5.48;N, 3.05 Found (%): C, 70.22; H, 5.60; N, 2.95

EXAMPLE 55N-(2,4-Difluorophenyl)-6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-acetamide(A)

Melting point: 168°-170° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.28 (3H,s), 3.47 (2H,s), 6.8-6.9(3H,m), 7.3-7.5 (4H,m), 7.5-7.6 (3H,m), 8.1-8.3 (1H,m), 8.45 (1H,bs)

Elemental analysis (for C₂₄ H₁₇ NO₃ F₂): Calculated (%): C, 71.11; H,4.23; N, 3.46 Found (%): C, 70.84; H, 4.25; N, 3.54

EXAMPLE 56 N-2,6-Bis(1-methylethyI)phenyl!-4-(2-methoxyphenyl)-1-oxo-1H-2-benzopyran-3-acetamide(B)

Melting point: 250°-252° C. (recrystallized from acetone-ethyl ether)NMR (200 MHz, CDCl₃) ppm: 1.08, 1.15 (total 12H, each d, J=6.6 Hz), 2.96(2H,m), 3.47 (1H,d,J=15.4 Hz), 3.60 (1H,d,J=15.4 Hz), 3.62 (3H,s),6.91-7.67 (10H,m), 8.38 (1H,dd,J=7.8, 1.7 Hz)

Elemental analysis (for C₃₀ H₃₁ NO₄): Calculated (%): C, 76.73; H, 6.65;N, 2.98 Found (%): (D, 76.58; H, 6.79; N, 3.00

EXAMPLE 57 N-2,6-Bis(1-methylethyl)phenyl!-6-chloro-4-phenyl-3-quinolineacetamide (B)

Melting point: 262°-263° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.12 (12H,d,J=6.8 Hz), 2.87 (2H, m),3.80 (2H,s), 6.45 (1H,s), 7.10-7.70 (10H,m), 8.11 (1H,d,J=9.0 Hz), 9.05(1H,s)

Elemental analysis (for C₂₉ H₂₉ N₂ OCl): Calculated (%): C, 76.22; H,6.40; N, 6.13 Found (%): C, 75.93; H, 6.65; N, 6.44

EXAMPLE 583,4-cis-N-(2,4-Difiuorophenyl)-3,4-dihydro-6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-acetamide(A)

Melting point: 194°-196° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 593,4-cis-6-Chloro-N-(2,4-difiuorophenyl)-3,4-dihydro-2-oxo-4-phenyl-2H-1-benzopyran-3-acetamide(A)

Melting point: 182°-184° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 60 3,4-trans-N-2,6-Bis(1-methylethyl)phenyl!-1,2,3,4-tetrahydro-1,6-dimethyl-2-oxo-4-phenyl-3-quinolineacetamide(A)

Melting point: 251°-252° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 0.90-1.30, 1.17 (total 12H,m,d,J=7.0Hz), 2.17, 2.21 (total 3H, each s), 2.61 (1H,dd,J=15, 6.2 Hz), 2.71 (1H,dd, J=15, 5.4 Hz), 3.06 (2H,m), 3.30-3.50 (1H,m), 3.35, 3.43 (total 3H,each s), 4.27, 4.38 (total 1H, each d,J=10Hz, J=11 Hz), 6.46, 6.59(total 1H, each s), 6.80-7.40 (11H,m)

EXAMPLE 61 3,4-trans-N-2,6-Bis(1-methylethyl)phenyl!-3-(6-chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenylcluinolin-3-yl)propionamide(A)

Melting point: 178°-180.5° C. (recrystallized from ethyl acetate-hexane)NMR (200 MHz, CDCl₃) ppm: 1.13 (6H,d,J=4.0 Hz), 1.16 (6H,d,J=3.2 Hz),1.70-2.30 (2H,m), 2.45-2.58 (2H,m), 2.92-3.20 (3H,m), 3.41 (3H,s), 4.01(1H,d,J=4.8 Hz), 6.90-7.40 (11H,m), 7.54 (1H,bs)

EXAMPLE 623,4-trans-3-(6-Chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenylquinolin-3-yl)-N-(2,4,6-trimethoxyphenyl)propionamide(A) A white foam NMR (200 MHz, CDCl₃) ppm: 1.67-2.20 (2H,m), 2.36-2.70(2H,m), 3.20-3.50 (1H, m), 3.39 (3H,s), 3.66 (6H,s), 3.79 (3H,s), 3.98(1H,bd), 6.11 (2H,s), 6.90-7.40 (9H,m) EXAMPLE 63N-(2,4-Difiuorophenyl)-1,2,3,4-tetrahydro-1,6-dimethyl-2-oxo-4-phenyl-3-quinoxalineacetamide(A)

Melting point: 94.5°-95.0° C. (recrystallized from ethyl ether-hexane)NMR (200 MHz, CDCl₃) ppm: 2.26 (3H,s), 2.60 (1H,dd,J=15, 8.5 Hz), 2.77(1H,dd,J=15, 5.5 Hz), 3.43 (3H,s), 5.01 (1H,dd,J=8.5, 5.5 Hz), 6.76-7.32(10H,m), 7.87 (1H,bs), 8.25 (1H,m)

EXAMPLE 64 N-2,6-Bis(1-methylethyl)phenyl!-1,2,3,4-tetrahydro-1,6-dimethyl-2-oxo-4-phenyl-3-quinoxalineacetamide(A)

Melting point: 186.5°-187.5° C. (recrystallized from ethyl ether-hexane)NMR (200 MHz, CDCl₃)ppm: 1.08 (6H,d,J=6.6 Hz), 1.15 (6H,d,J=7.0 Hz),2.28 (3H,s), 2.59 (1H,dd,J=15, 9.4 Hz), 2.81 (1H,dd,J=15, 4.6 Hz), 3.06(2H,m), 3.42 (3H,s), 5.16 (1H,dd,J=9.4, 4.6 Hz), 6.90-7.30 (12H,m)

EXAMPLE 651,2,3,4-Tetrahydro-1,6-dimethyl-2-oxo-4-phenyl-N-(2,4,6-trimethoxyphenyl)-3-quinoxalineacetamide(A)

Melting point: 237°-238° C. (recrystallized from THF-isopropyl ether)NMR (200 MHz, CDCl₃) ppm: 2.26 (3H,s), 2.49 (1H,dd,J=14, 10 Hz), 2.71(1H,dd,J=14, 3.6 Hz), 3.41 (3H,s), 3.63 (6H,s), 3.79 (3H,s), 5.11(1H,dd, J=10, 3.6 Hz), 6.11 (2H,s), 6.68 (1H,bs), 6.87-7.28 (8H,m)

EXAMPLE 66N-(2,6-Dimethoxyphenyl)-1,2,3,4-tetrahydro-1,6-dimethyl-2-oxo-4-phenyl-3-quinoxalineacetamide(A)

Melting point: 139.5°-140.5° C. (recrystallized from ethylacetate-isopropyl ether) NMR (200 MHz, CDCl₃) ppm: 2.26 (3H,s),2.40-2.80 (2H,m), 3.41 (3H,s), 3.67 (6H,s), 5.10 (1H,bdd), 6.54(2H,d,J=8.4 Hz), 6.80-7.30 (10 H,m)

EXAMPLE 676-Chloro-N-(2,6-dimethoxyphenyl)-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinoxalineacetamide(A)

Melting point: 212.5°-213.2° C. (recrystallized from ethylacetate-isopropyl ether) NMR (200 MHz, CDCl₃) ppm: 2.35-2.90 (2H,m),3.41 (3H,s), 3.69 (6H,s), 5.08 (1H,m), 6.53 (2H,d,J=8.0 Hz), 6.72(1H,bs), 6.95-7.30 (9H,m)

EXAMPLE 68 N-2,6-Bis(1-methylethyl)phenyl!-6-chloro-1,2-dihydro-2-oxo-4-phenyl-3-quinolineacetamide(A)

Melting point: 333°-337° C. (recrystallized frommethanol-chloroform-isopropyl ether) NMR (200 MHz, CDCl₃ -DMSO-d₆) ppm:1.11 (12H,d,J=7.0 Hz), 3.54 (2H,s), 7.0-7.6 (11H,m), 8.84 (1H,b), 12.2(1H,b)

EXAMPLE 691,2-Dihydro-1,6-dimethyl-2-oxo-4-phenyl-N-(2,4,6-trimethoxyphenyl)-3-quinolineacetamide(A)

Melting point: 275.5°-277.0° C. (recrystallized from ethylacetate-isopropyl ether) NMR (200 MHz, CDCl₃) ppm: 2.28 (3H,s), 3.54(2H,s), 3.73 (3H,s), 3.77 (6H,s), 3.86 (3H,s), 6.10 (2H,s), 6.96(1H,bs), 7.25-7.55 (8H,m)

EXAMPLE 70N-(2,6-Dimethoxyphenyl)-1,2-dihydro-1,6-dimethyl-2-oxo-4-phenyl-3-quinolineacetamide(A)

Melting point: 212.0°-213.5° C. (recrystallized from ethylacetate-isopropyl ether) NMR (200 MHz, CDCl₃) ppm: 2.28 (3H,s), 3.54(2H,s), 3.76 (6H,s), 3.86 (3H,s), 6.53 (2H,d,J=8.4 Hz), 6.96 (1H,bs),7.10 (1H,t,J=8.4 Hz), 7.30-7.60 (8H,m)

EXAMPLE 71 N-2,6-Bis(1-methylethyl)phenyl!-6-chloro-2-methoxy-4-phenyl-3-quinolineacetnmide(A)

Melting point: 256°-259° C. (recrystallized from ethyl acetate-hexane)NMR (200 MHz, CDCl₃) ppm: 1.14 (12H,d,J=7.0 Hz), 3.69 (2H,s), 4.19(3H,s), 7.1-7.2 (2H,m), 7.2-7.4 (5H,m), 7.5-7.6 (3H,m), 7.84 (1H,m)

EXAMPLE 726-Chloro-N-(2,6-dimethoxyphenyl)-2-methoxy-4-phenyl-3-quinolineacetamide(A)

Melting point: 220°-222° C. (recrystallized from ethyl acetate-hexane)NMR (200 MHz, CDCl₃) ppm: 3.63 (2H, b), 3.79 (6H, s), 4.18 (3H, s), 6.55(2H, d, J=8.6 Hz), 7.15 (1H, m), 7.28 (1H, m), 7.3-7.5 (2H, m), 7.5-7.6(4H, m), 7.83 (1H, d, J=9.0 Hz)

EXAMPLE 73N-(2,4-Difluorophenyl)-4-(2-methoxyphenyl)-1-oxo-1H-2-benzopyran-3-acetamide(A)

Melting point: 214°-216° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 3.51 (2H, s), 3.70 (3H, s), 6.8-6.9(2H, m), 6.96 (1H, d, J=10.4 Hz), 7.0-7.2 (2H, m), 7.26. (1H, m),7.4-7.7 (3H, m), 7.75 (1H, b), 8.15 (1H, m), 8.36 (1H, dd, J=7.6 Hz, 1.2Hz)

EXAMPLE 74N-(2,6-Dimethoxyphenyl)-4-(2-methoxyphenyl)-1-oxo-1H-2-benzopyran-3-acetamide(A)

Melting point: 210°-213° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 3.46 (2H, m), 3.68 (3H, s), 3.77 (6H,s), 6.54 (2H, d, J=8.4 Hz), 6.93 (1H, d, J=8.2 Hz), 7.0-7.2 (3H, m),7.35 (1H, dd, J=7.4 Hz, 1.6 Hz), 7.4-7.6 (3H, m), 8.35 (1H, m)

EXAMPLE 754-(2-Methoxyphenyl)-1-oxo-N-(2,4,6-trimethoxyphenyl)-1H-2-benzopyran-3-acetamide(A)

Melting point: 229°-231° C. (recrystallized from ethylacetate-chloroform-isopropyl ether) NMR (200 MHz, CDCl₃) ppm: 3.47 (2H,m), 3.67 (3H, s), 3.76 (3H, s), 3.78 (6H, s), 6.11 (2H, s), 6.9-7.2 (3H,m), 7.35 (1H, d, J=6.8 Hz), 7.4-7.6 (3H, m), 8.36 (1H, m)

EXAMPLE 766-Chloro-N-(2,6-dimethoxyphenyl)-1-oxo-4-phenyl-1H-2-benzopyrau-3-acetamide(A)

Melting point: 245°-247° C. (recrystallized from chloroform-isopropylether) NMR (200 MHz, CDCl₃) ppm: 3.45 (2H, m), 3.78 (6H, s), 6.54 (2H,d, J=8.4 Hz), 7.01 (1H, d, J=1.4 Hz), 7.18 (1H, t, J=8.6 Hz), 7.4-7.6(6H, m), 8.27 (1H, d, J=8.4 Hz)

EXAMPLE 776-Chloro-N-(2,6-ethoxyphenyl)-1-oxo-4-phenyl-1H-2-benzopyran-3-acetamide(B)

Melting point: 209°-210° C. (recrystallized from ethanol) NMR (200 MHz,CDCl₃) ppm: 1.31 (6H, t, J=7 Hz), 3.44 (2H, b), 4.01 (4H, q, J=7Hz),6.52 (2H, d, J=8.4 Hz), 7.02-7.52 (9H, m), 8.27 (1H, d, J=8.4 Hz)

EXAMPLE 78 6-Chloro-N-4-(N,N-dimethylamino)phenyl!-2-oxo-4-phenyl-2H-1-benzopyran-3-acetamide(A)

Melting point: 220°-222° C. (recrystallized from ethylacetate-chloroform-isopropyl ether) NMR (200 MHz, CDCl₃) ppm: 2.90 (6H,s), 3.42 (2H, s), 6.68 (2H, d, J=9.0 Hz), 7.04 (1H, d, J=2.0 Hz),7.3-7.6 (9H, m), 7.95 (1H, b)

EXAMPLE 796-Chloro-N-(2,6-dimethoxyphenyl)-2-oxo-4-phenyl-2H-1-benzopyran-3-acetamide(A)

Melting point: 245°-247° C. (recrystallized from chloroform-isopropylether) NMR (200 MHz, CDCl₃) ppm: 3.47 (2H, b), 3.78 (6H, s), 6.55 (2H,d, J=8.4 Hz), 7.03 (1H, d, J=1.8 Hz), 7.16 (1H, t, J=8.4 Hz), 7.3-7.5(4H, m), 7.5-7.6 (3H, m)

EXAMPLE 80 N-4-(N,N-Dimethylamino)phenyl!-6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-acetamide(A)

Melting point: 227°-228° C. (recrystallized from ethylacetate-chloroform-isopropyl ether) NMR (200 MHz, CDCl₃) ppm: 2.27 (3H,s), 2.89 (6H, s), 3.41 (2H, s), 6.68 (2H, d, J=8.8 Hz), 6.84 (1H, s),7.3-7.4 (6H, m), 7.5-7.6 (3H, m), 8.18 (1H, b)

EXAMPLE 81N-(2,6-Dimethoxyphenyl)-6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-acetamid(A)

Melting point: 257°-258° C. (recrystallized from chloroform-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.27 (3H, s), 3.46 (2H, b), 3.77 (6H,s), 6.54 (2H, cl, J=8.4 Hz), 6.83 (1H, s), 7.14 (1H, t, J=8.4 Hz),7.2-7.3 (2H, m), 7.4-7.6 (5H, m)

EXAMPLE 82 N-2,6-Bis(1-methylethyl)phenyl!-6-chloro-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-acetamide(A)

Melting point: 241°-243° C. (recrystallized from acetone-methanol) NMR(200 MHz, CDCl₃) ppm: 1.13 (total 12H, d, J=6.8 Hz, 1.0-1.1, m), 2.03,2.09 (total 3H, each s), 3.00 (2H, m), 3.38 (1H, d, J=13.8 Hz), 3.58(1H, d, J=13.8 Hz), 6.85 (1H, d, J=2.4 Hz), 7.1-7.2 (3H, m), 7.3-7.5(6H, m)

EXAMPLE 836-Chloro-N-(2,4-difluorophenyl)-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-acetamide(A)

Melting point: 186°-188° C. (recrystallized from chloroform-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.09 (3H, s), 3.35 (1H, d, J=14.1 Hz),3.50 (1H, d, J=13.9 Hz), 6.7-6.9 (3H, m), 7.17 (1H, m), 7.3-7.5 (5H, m),8.0-8.2 (2H, m)

EXAMPLE 846-Chloro-N-(2,6-dimethoxyphenyl)-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-acetamide(A)

Melting point: 196°-198° C. (recrystallized From ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.09 (3H, s), 3.4 (2H, m), 3.75 (6H,s), 6.53 (2H, d, J=8.4 Hz), 6.82 (1H, d, J=2.2 Hz), 7.14 (1H, t, J=8.4Hz), 7.2 (1H, m), 7.3-7.5 (5H, m)

EXAMPLE 856-Chloro-4-(2-methylphenyl)-2-oxo-N-(2,4,6-trimethoxyphenyl)-2H-1-benzopyran-3-acetamide(A)

Melting point: 183°-185° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.08 (3H, s), 3.4 (2H, m), 3.74 (3H,s), 3.78 (6H, s), 6.09 (2H, s), 6.81 (1H, m), 7.2-7.5 (6H, m)

EXAMPLE 866-Chloro-N-(2,6-dimethylphenyl)-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-acetamide(A)

Melting point: 235°-238° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.10 (3H, s), 2.17 (6H, s), 3.36 (1H,d, J=13.8 Hz), 3.54 (1H, d, J=14.0 Hz), 6.86 (1H, d, J=2.4Hz), 7.04(31H, m), 7.2-7.3 (1H, m), 7.3-7.5 (5H, m)

EXAMPLE 87 6-Chloro-4-(2-methylphenyl)-2-oxo-N-(2,4,6-trimethylphenyl)-2H-1-benzopyran-3-acetamide(A)

Melting point: 238°-241° C. (recrystallized from ethylacetate-acetone-isopropyl ether) NMR (200 MHz, CDCl₃) ppm: 2.10 (3H, s),2.12 (6H, s), 2.23 (3H, s), 3.34 (1H, d, J=14.0 Hz), 3.52 (1H, d, J=13.8Hz), 6.85 (3H, m), 7.2-7.3 (1H, m), 7.3-7.5 (5H, m)

EXAMPLE 886-Chloro-N-(2,6-diethoxyphenyl)-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-acetamide(A)

Melting point: 200°-202° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.29 (6H, t, J=7.0 Hz), 2.08 (3H, s),3.44 (2H, b), 8.98 (4H, q, J=7.0 Hz), 6.50 (2H, d, J=8.4 Hz), 6.82 (1H,m), 7.09 (1H, t, J=8.6 Hz), 7.2-7.5 (6H, m)

EXAMPLE 896-Chloro-N-(2,6-diethoxy-4-fluorophenyl)-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-acetamide(A)

Melting point: 208°-209° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.29 (6H, t, J=7.0 Hz), 2.08 (3H, s),3.32 (1H, bd), 3.53 (1H, bd), 3.93 (4H, q, J=7.0 Hz), 6.23 (2H, d, J=11Hz), 6.83 (2H, bs), 7.19-7.50 (7H, m)

EXAMPLE 90 N-3,5-Bis(trifluoromethyl)phenyl!-6-chloro-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-acetamide(A)

Melting point: 205°-206° C. (recrystalized from ethyl acetate-isopropylether)

EXAMPLE 91 N-2,6-Bis(1-methylethyl)phenyl!-6-chloro-4-(2-methylphenyl)-1-quinolineacetamide(B)

Melting point: 208°-210° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.11 (6H, d, J=7.0 Hz), 1.13 (6H, d,J=7.0 Hz), 1.97 (3H, s), 2.85 (2H, m), 3.60 (1H, d, J=16Hz), 3.79 (1H,d, J=16 Hz), 6.43 (1H, bs), 7.00-7.70 (5H, m), 8.12 (1H, d, J=8.8 Hz),9.08 (1H, s)

EXAMPLE 92 N-2,6-Bis(1-methylethyl)phenyl!-6-chloro-4-(2-methoxyphenyl)-2-oxo-2H-1-benzopyran-3-acetamide(A)

Melting point: 303°-305° C. (recrystallized from chloroform) NMR (200MHz, CDCl₃) ppm: 1.13 (dd, 12H, J=2.4, 6.8 Hz), 2.90-3.05 (m, 2H), 3.38(d, 1H, J=13.8 Hz), 3.65 (d, 1H, J=14.0 Hz), 3.71 (s, 3H), 6.95 (d, 1H,J=2.4 Hz), 7.06-7.18 (m, 4H), 7.22-7.30 (m, 2H), 7.37 (d, 1H, J=8.8 Hz),7.44-7.58 (m, 2H)

EXAMPLE 936-Chloro-N-(2,6-diethoxyphenyl)-4-(2-methoxyphenyl)-2-oxo-2H-1-benzopyran-3-acetamide(A)

Melting point: 226°-227° C. (recrystallized from ethyl acetate-methanol)NMR (200 MHz, CDCl₃) ppm: 1.29 (6H, t, J=7.0 Hz), 3.20-3.38 (1H, m),3.56-3.70 (1H, m), 3.69 (3H, s), 3.98 (4H, q, J=7.0 Hz), 6.51 (2H, d,J=8.4 Hz), 6.92 (1H, d, J=2.2 Hz), 7.00-7.18 (3H, m), 7.28-7.56 (4H, m)

EXAMPLE 94 N-2,6-Bis(1-methylethyl)phenyl!-6-chloro-2-oxo-4-(2-trifluoromethylphenyl)-2H-1-benzopyran-3-acetamide(A)

Melting point:246°-247° C. (recrystallized from ethyl acetate) NMR (200MHz, CDCl₃) ppm: 1.12 (12H, t, J=6.4 Hz), 2.88-3.06 (2H, m), 3.07 (1H,d, J=14.0 Hz), 3.79 (1H, d, J=13.8 Hz), 6.72 (1H, d, J=2.4 Hz), 7.13(1H, d, J=7.0 Hz), 7.20-7.30 (1H, m), 7.32-7.50 (4H, m), 7.64-7.74 (2H,m), 7.84-7.92 (1H, m)

EXAMPLE 956-Chloro-N-(2,6-diethoxyphenyl)-2-oxo-4-(2-trifluoromethylphenyl)-2H-1-benzopyran-3-acetamide(A)

Melting point: 197°-199° C. (recrystallized from ethyl ether--ethylacetate) NMR (200 MHz, CDCl₃) ppm: 1.27 (6H, t, J=7.0 Hz), 2.94-3.08(1H, m), 3.70-3.88 (1H, m), 3.97 (4H, q, J=7.0 Hz), 6.50 (2H, d,j=8.4Hz), J=8.4 Hz), 6.68 (1H, s), 7.09 (1H, t, J=8.0 Hz), 7.32 (2H, d,J=8.6 Hz), 7.44 (1H, dd, J=2.2, 8.6 Hz), 7.46-7.58 (1H, m), 7.58-7.76(2H, m), 7.86 (1H, d, J=7.6 Hz)

EXAMPLE 966-Chloro-N-(2,6-diethoxy-4-fluorophenyl)-2-oxo-4-(2-trifluoromethylphenyl)-2H-1-benzopyran-3-acetamide(A)

Melting point: 199°-200° C. (recrystallized from ethyl ether-hexane) NMR(200 MHz, CDCl₃) ppm: 1.28 (6H, t, J=7.0 Hz), 3.01 (1H, bd), 3.75 (1H,bd), 3.93 (4H, q, J=7.0 Hz), 6.23 (2H, d, J=11 Hz), 6.69 (1H, bs),7.18-7.90 (7H, m)

EXAMPLE 976-Chloro-4-(2-methoxyphenyl)-2-oxo-N-(2,4,6-trifluolophenyl)-2H-1-benzopyran-3-acetamide(A)

Melting point: 243°-245° C. (recrystallized from ethyl acetate) NMR (200MHz, CDCl₃) ppm: 3.41 (1H, d, J=14.2 Hz), 3.55 (1H, d, J=14.0 35 Hz),3.73 (3H, s), 6.70 (2H, ddd, J=2.0, 7.6, 8.8 Hz), 6.97 (1H, d, J=2.4Hz), 7.09 (1H, d, J=8.6 Hz), 7.17 (1H, d, J=7.0 Hz), 7.21 (1H, dd,J=2.0, 4.2 Hz), 7.36 (1H, d, J=8.8 Hz), 7.48 (1H, dd, J=2.4 Hz), 7.54(1H, ddd, J=2.2, 7.0, 8.4 Hz), 7.75 (1H, bs)

EXAMPLE 986-Chloro-N-(2,6-dimethoxybenzyl)-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-acetamide

6-Chloro-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-acetic acid wasreacted with 2,6-dimethoxybenzylamine by a method similar to Example1(A) to yield the title compound.

Melting point: 194°-196° C. (recrystallized from ethylacetate-methanol-isopropyl ether) NMR (200 MHz, CDCl3) ppm: 2.05 (3H,s), 3.11 (1H, d, J=14.0 Hz), 3.27 (1H, d, J=14.0 Hz), 3.81 (6H, s), 4.49(2H, d, J=5.4 Hz), 6.35 (1H, b), 6.54 (2H, d, J=8.4 Hz), 6.81 (1H, d,J=2.2 Hz), 7.2-7.5 (7H, m)

EXAMPLE 99 N-2,6-Bis(1-methylethyl)phenyl!-6-chloro-1,2-dihydro-1-methyl-4-phenyl-3-quinolineacetamide

A mixture of the compound obtained in Example 57 (150 mg), dioxane (5ml) and methyl iodide (1.5 ml) was refiuxed for 2 hours while heating.Upon solvent removal by distillation, a quaternary salt (iodide),resulting from 1-methylation of the compound of Example 57, was obtainedas yellow crystals. To a solution of this quaternary salt in methanol (5ml) was added sodium borohydride (30 mg) at 0° C., followed by stirringfor 20 minutes. The reaction mixture was acidified with dilutehydrochloric acid and then alkalinized with aqueous potassium carbonate,followed by extraction with ethyl acetate. The extract was washed withwater and dried, after which the solvent was distilled off, to yield thetitle compound as colorless crystals (90 mg).

Melting point: 192°-194° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.15 (12H, d, J=6.6 Hz), 2.86 (3H, s),2.95 (2H, m), 3.17 (2H, s), 4.08 (2H, s), 6.45-6.58 (2H, m), 7.00-7.50(10H, m)

Elemental analysis (for C₃₀ H₃₃ N₂ OCl·0.2i-Pr₂ O):

Calculated (%): C, 75.94; H, 7.31; N, 5.68

Found (%): C, 75.71; H, 7.13; N, 6.02

EXAMPLE 100 N-2,6-Bis(1-methylethyl)phenyl!-6-chloro-1,2-dihydro-1-methyl-4-(2-methylphenyl)-3-quinolineacetamide

N-2,6-Bis(1-methylethyl)phenyl!-6-chloro-4-(2-methylphenyl)-3-quinolineacetamide(Example 91) was reacted by a method similar to Example 99 to yield thetitle compound.

Melting point: 159.5°-160.5° C. (recrystallized from ethylacetate-isopropyl ether) NMR (200 MHz, CDCl₃) ppm: 1.14 (6H, d, J=3.6Hz), 1.17 (6H, d, J=3.6 Hz), 2.15 (3H, s), 2.87 (3H, s), 2.95 (2H, m),3.05 (2H, m), 4.11 (2H, s), 6.36(1H, d, J=2.2 Hz), 6.53 (1H, d, J=8.8Hz), 6.97 (1H, bs), 7.00-7.40 (8H, m)

EXAMPLE 101 N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamide

To a solution of2-methyl-4-(2-methylphenyl)-l(2H)-isoquinolinone-3-carboxylic acid (293mg) fn THF (10 ml) were added oxalyl chloride (0.104 ml) and DMF (onedrop) at room temperature, followed by stirring for 1 hour. After thesolvent was distilled off, the residue was dissolved in dichloromethane(10 ml). To this solution was added a solution of3,5-bis(trifluoromethyl)benzylamine (340 mg) and triethylamine (0.154ml) in dichloromethane (5 ml), followed by stirring at room temperaturefor 5 hours. After the solvent was distilled off, ethyl acetate wasadded to the residue. This mixture was washed successively with water,dilute hydrochloric acid, water, aqueous sodium hydrogen carbonate andwater and then dried, after which the solvent was distilled off, toyield fie title compound as colorless crystals (250 mg).

Melting point: 168.5°-170.0° C. (recrystallized from ethylacetate-hexane) NMR (200 MHz, CDCl₃) ppm: 2.02 (3H, s), 3.59 (3H, s),4.24 (1H, dd, J: 14.6, 5.6 Hz), 4.42 (1H, dd, J=14.6, 5.6 Hz), 6.15 (1H,b, NH), 6.89 (1H, m), 7.09 (4H, m), 7.50 (4H, m), 7.79 (1H, s), 8.44(1H, m)

Elemental analysis (for C₂₇ H₂₀ N₂ O₂ F₆):

Calculated: C, 62.55; H, 3.89; N, 5.40

Found: C, 62.29; H, 4.12; N, 5.68

EXAMPLE 102 N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N,2-dimethyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamideMethod C

A mixture of the compound (156 mg) obtained in Example 101, sodiumhydride (60% in oil) (12 mg) and DMF (5 ml) was stirred at roomtemperature for 30 minutes, and methyl iodide (0.5 ml) was added,followed by stirring at room temperature for 1 hour. The reactionmixture was poured into water and extracted with ethyl acetate, and theextract was washed with water and then dried, followed by solventremoval by distillation, to yield the title compound as colorlesscrystals (156 mg).

Method D

Using N- 3,5-bis(trifluoromethyl)benzyl!methylamine in place of3,5-bis(trifluoromethyl)benzylamine,2-methyl-4-(2-methylphenyl)-1(2H)-isoquinolinone-3-carboxylic acid wasamidated in substantially the same manner as in Example 101 to yield thetitle compound as colorless crystals.

Melting point: 76°-78° C. (recrystallized from hexane) NMR (200 MHz,CDCl₃) ppm: 2.01 (1.5H, s), 2.12 (1.5H, s), 2.77 (1.5H, s), 2.97 (1.5H,s), 3.58 (1.5H, s), 3.60 (1.5H, s), 4.10 (0.5H, d, J=14.4 Hz), 4.26(0.5H, d, J=14.4 Hz), 4.78 (0.5H, d, J=14.4 Hz), 4.96 (0.5H, d, J=14.4Hz), 6.86-7.02 (2H, m), 7.12-7.32 (3H, m), 7.48-7.57 (4H, m), 7.79 (1H,s), 8.51 (1H, m)

Elemental analysis (for C₂₈ H₂₂ N₂ O₂ F₆):

Calculated: C, 63.16; H, 4.16; N, 5.26

Found: C, 63.40; H, 4.37; N, 5.02

The compounds of Examples 103 to 188 were obtained by reacting1(2H)-isoquinoline-3-carboxylic acids having respective correspondingsubstituents with amines in the same manner (amidation) as in Example101 or method D of Example 102, or by reacting amide compounds havingrespective corresponding substituents with alkylating agents in the samemanner (alkylation) as method C of Example 102. With respect to Examples103 to 188, the name of the compound is followed by the symbol C! whenthe compound was produced by alkylation, other production examples beingbased on amidation.

EXAMPLE 103N-Benzyl-1,2-dihydro-N,2-dimethyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamide

Melting point: 172°-173.5° C. (recrystallized from ethyl acetate) NMR(200 MMz, CDCl₃) ppm: 2.22 (3H, s), 2.86 (3H, s), 3.60 (3H, s), 3.96(1H, d, J=14.6 Hz), 5.05 (1H, d, J=14.6 Hz), 6.66 (1H, dd, J=8.0, 2.0Hz), 6.92-7.56 (11H, m), 8.53 (1H, m)

Elemental analysis (for C₂₆ H₂₄ N₂ O₂ ·0.2H₂ O):

Calculated: C, 78.05; H, 6.15; N, 7.00

Found: C, 78.25; H, 6.11; N, 7.00

EXAMPLE 1041,2-Dihydro-N-(2-methoxybenzyl)-N,2-dimethyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamideC!

Melting point: 153°-154.5° C. (recrystallized from ethyl acetate) NMR(200 MHz, CDCl₃) ppm: 2.04 (1.5H, s), 2.19 (1.5H, s), 2.74 (1.5H, s),2.89 (1.5H, s), 3.59 (1.5H, s), 3.62 (1.5H, s), 3.77 (1.5H, s), 3.78(1.5H, s), 4.35 (1H, dd, J=15.2, 7.6 Hz), 4.73 (1H, dd, J=15.0, 5.8 Hz),6.08 (0.5H, d, J=7.2 Hz), 6.24 (0.5H, d, J=7.6 Hz), 6.56-7.56 (10H, m),8.51 (1H, m)

Elemental analysis (for C₂₇ H₂₆ N₂ O₃):

Calculated: C, 76.03; H, 6.14; N, 6.57

Found: C, 75.66; H, 6.20; N, 6.56

EXAMPLE 105N-(2-Chlorobenzyl)-1,2-dihydro-N,2-dimethyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamideC!

Melting point: 143°-144° C. (recrystallized from ethyl acetate) NMR (200MHz, CDCl₃) ppm: 2.05 (1.5H, s), 2.20 (1.5H, s), 2.79 (1.5H, s), 2.94(1.5H, s), 3.63 (1.5H, s), 3.65 (1.5H, s), 4.26 (1H, d, J=15.4 Hz), 5.08(1H, d, J=16.2 Hz), 5.92 (0.5H, d, J=8.0.Hz), 6.07 (0.5H, d, J=8.0 Hz),6.89-7.59 (10H, m), 8.53 (1H, m)

Elemental analysis (for C₂₆ H₂₃ N₂ O₂ Cl):

Calculated: C, 72.47; H, 5.38; N, 6.50

Found: C, 72.46; H, 5.37; N, 6.73

EXAMPLE 1061,2-Dihydro-N-(3,5-dimethylbenzyl)-N,2-dimethyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamideC!

Melting point: 135°-136° C. (recrystallized from ethyl acetate-hexane)NMR (200 MHz, CDCl₃) ppm: 2.01 (1.5H, s), 2.20 (1.5H, s), 2.25 (6H, s),2.66 (1.5H, s), 2.84 (1.5H, s), 3.58 (1.5H, s), 3.61 (1H, s), 4.08 (1H,dd, J=14.0, 8.8 Hz), 4.71 (1H, t, J=12.8 Hz), 6.45 (1H, s), 6.52 (1H,s), 6.87-7.55 (8H, m), 8.52 (1H, m)

Elemental analysis (for C₂₈ H₂₈ N₂ O₂):

Calculated: C, 79.22; H, 6.65; N, 6.60

Found: C, 78.85; H, 6.68; N, 6.64

EXAMPLE 107N-Ethyl-1,2-dihydro-N-(2-methoxybenzyl)-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamideC!

Melting point: 119°-120° C. (recrystallized from ethyl ether-hexane) NMR(200 MHz, CDCl₃) ppm: 0.97 (0.9H, t, J=7.2 Hz), 1.12 (2.1H, t, J=7.2Hz), 2.01 (0.9H, s), 2.19 (2.1H, s), 2.85-3.20 (2H, m), 3.62 (2.1H, s),3.63 (0.9H, s), 3.79 (3H, s), 4.30 (0.7H, d, J=15.8 Hz), 4.35 (0.3H, d,J=15.8 Hz), 4.87 (0.3H, d, J=15.8 Hz), 4.93 (0.7H, d, J=15.8 Hz), 5.88(1H, m), 6.56-7.58 (10H, m), 8.53 (1H, m)

Elemental analysis (for C₂₈ H₂₈ N₂ O₃):

Calculated: C, 76.34; H, 6.41; N, 6.36

Found: C, 76.57; H, 6.48; N, 6.51

EXAMPLE 1081,2-Dihydro-N-(2-methoxybenzyl)-N,2-dimethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamideC!

Melting point: 146.5°-147.5° C. (recrystallized from ethyl acetate) NMR(200 MHz, CDCl₃) ppm: 2.72 (3H, s), 3.62 (3H, s), 3.77 (3H, s), 4.40(1H, d, J=15.2 Hz), 4.64 (1H, d, J=15.2 Hz); 6.23 (1H, d, J=6.2 Hz),6.69 (1H, t, J=7.4 Hz), 6.78 (1H, d, J=8.4 Hz), 7.15-7.31 (3H, m),7.41-7.60 (6H, m), 8.52 (1H, m)

Elemental analysis (for C₂₆ H₂₄ N₂ O₃):

Calculated: C, 75.71; H, 5.86; N, 6.79

Found: C, 75.43; H, 5.83; N, 6.90

EXAMPLE 1091,2-Dihydro-N-(4-methoxybenzyl)-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide

Melting point: 240°-242.5° C. (recrystallized from THF-isopropyl ether)NMR (200 MHz, CDCl₃) ppm: 2.22 (3H, s), 2.34 (3H, s), 3.53 (3H, s), 3.79(3H, s), 4.17 (2H, d, J=5.4 Hz), 6.15 (1H, bt, J=5.4 Hz), 6.72 (4H, s),6.89 (1H, s), 7.30-7.50 (5H, m), 8.14 (1H, s)

Elemental analysis (for C₂₇ H₂₆ N₂ O₃):

Calculated: C, 76.03; H, 6.14; N, 6.57

Found: C, 75.70; H, 6.32; N, 6.47

EXAMPLE 1101,2-Dihydro-N-(2-methoxybenzyl)-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide

Melting point: 229°-231.5° C. (recrystallized from THF-ethyl ether) NMR(200 MHz, CDCl₃) ppm: 2.23 (3H, s), 2.36 (3H, s), 3.57 (3H, s), 3.75(3H, s), 4.24 (2H, d, J=6.4 Hz), 6.21 (1H, bt), 6.70-6.90 (3H, m), 6.93(1H, s), 7.15-7.30 (6H, m), 8.21 (1H, s)

Elemental analysis (for C₂₇ H₂₆ N₂ O₃):

Calculated: C, 76.03; H, 6.14; N, 6.57

Found: C, 75.95; H, 6.18; N, 6.53

EXAMPLE 1111,2-Dihydro-N-(2-methoxybenzyl)-N,2,6,7-tetramethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamideC!

Melting point: 123°-124° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.26 (3H, s), 2.40 (3H, s), 2.70 (3H,s), 3.60 (3H, s), 3.77 (3H, s), 4.38 (1H, d, J=15 Hz), 4.64 (1H, d, J=15Hz), 6.20 (1H, dd, J=7.2, 1.4 Hz), 6.69 (1H, dt, J=1.0, 7.6 Hz), 6.79(1H, d, J=7.4 Hz), 6.97 (1H, s), 7.10-7.35 (2H, m), 7.35-7.55 (4H, m),8.27 (1H, s)

Elemental analysis (for C₂₈ H₂₈ N₂ O₃):

Calculated: C, 76.34; H, 6.41; N, 6.36

Found: C, 76.00; H, 6.70; N, 6.06

EXAMPLE 112 N- 3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N,2,6,7-tetramethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide C!

Melting point: 148°-149° C. (recrystallized from ethyl ether-hexane) NMR(200 MHz, CDCl₃) ppm: 2.26 (3H, s), 2.40 (3H, s), 2.76 (3H, s), 3.58(3H, s), 4.26 (1H, d, J=15 Hz), 4.74 (1H, d, J=15 Hz), 6.94 (1H, s),7.15-7.45 (5H, m), 7.50 (2H, s), 7.80 (1H, s), 8.27 (1H, s)

Elemental analysis (for C₂₉ H₂₄ N₂ O₂ F₆):

Calculated: C, 63.73; It, 4.43; N, 5.13

Found: C, 63.98; H, 4.59; N, 5.13

EXAMPLE 1131,2-Dihydro-N-(2-methoxybenzyl)-2-methyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide

Melting point: 220-221° C. (recrystallized from ethyl acetate)

EXAMPLE 1141,2-Dihydro-N-(2-methoxybenzyl)-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamide

Melting point: 237°-239° C. (recrystallized from ethyl acetate)

EXAMPLE 115N-(2-Chlorobenzyl)-1,2-dihydro-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamide

Melting point: 230°-231° C. (recrystallized from ethyl acetate)

EXAMPLE 1161,2-Dihydro-N-(3,5-dimethylbenzyl)-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamide

Melting point: 176.5°-177.5° C. (recrystallized from ethyl acetate)

EXAMPLE 117N-Benzyl-1,2-dihydro-N-(2-methoxybenzyl)-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamideA!

Melting point: 118°-120° C. (recrystallized from ethyl ether-hexane)

EXAMPLE 1181,2-Dihydro-N-(4-methoxybenzyl)-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamide

Melting point: 178°-179.5° C. (recrystallized from ethyl acetate)

EXAMPLE 119N-Benzyl-1,2-dihydro-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamide

Melting point: 170°-172° C. (recrystallized from ethyl acetate)

EXAMPLE 120N-Benzyl-4-(2-ethylphenyl)-1,2-dihydro-2-methyl-1-oxo-3-isoquinolinecarboxamide

Melting point: 177°-179° C. (recrystallized from ethyl acetate)

EXAMPLE 1214-(2-Ethylphenyl)-1,2-dihydro-N-(4-methoxybenzyl)-2-methyl-1-oxo-3-isoquinolinecarboxamide

Melting point: 195°-196° C. (recrystallized from ethyl acetate)

EXAMPLE 122 N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-2-methyl-4-(2,6-dimethylphenyl)-1-oxo-3-isoquinolinecarboxamide

Melting point: 225.5°-226.5° C. (recrystallized from ethyl acetate)

Elemental analysis (for C₂₈ H₂₂ N₂ O₂ F₆):

Calculated: C, 63.16; H, 4.16; N, 5.26

Found: C, 62.94; H, 4.18; N, 5.15

EXAMPLE 123 N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-4-(2,6-dimethylphenyl)-N,2-dimethyl-1-oxo-3-isoquinolinecarboxamideC!

Melting point: 121°-124° C. (recrystallized from ethyl ether)

EXAMPLE 1241,2-Dihydro-N-(2-methoxybenzyl)-2-methyl-4-(2,6-dimethylphenyl)-1-oxo-3-isoquinolinecarboxamide

Melting point: 175°-177° C. (recrystallized from ethyl acetate)

EXAMPLE 1251,2-Dihydro-4-(2,6-dimethylphenyl)-N-(2-methoxybenzyl)-N,2-dimethyl-1-oxo-3-isoquinolinecarboxamideC!

Melting point: 192°-194° C. (recrystallized from ethyl acetate-ethylether)

EXAMPLE 1261,2-Dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-N-(2-phenylethyl)-3-isoquinolinecarboxamide

Melting point: 225°-226.5° C. (recrystallized from ethylacetate-isopropyl ether)

EXAMPLE 1271,2-Dihydro-2,6,7-trimethyl-N-(4-methylbenzyl)-1-oxo-4-phenyl-3-isoquinolinecarboxamide

Melting point: 240°-242° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 1281,2-Dihydro-N-(3-methoxybenzyl)-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide

Melting point: 201°-203° C. (recrystallized from THF-ethyl ether)

EXAMPLE 129N-(4-Chlorobenzyl)-1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide

Melting point: 243.7°-245.7° C. (recrystallized from THF-isopropylether)

EXAMPLE 130N-(3-Chlorobenzyl)-1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide

Melting point: 213°-214° C. (recrystallized from THF-ethyl ether)

EXAMPLE 131N-(2-Chlorobenzyl)-1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide

Melting point: 259.5°-260.5° C. (recrystallized from THF-ethyl ether)

EXAMPLE 1321,2-Dihydro-N,2,6,7-tetramethyl-N-(4-methylbenzyl)-1-oxo-4-phenyl-3-isoquinolinecarboxamideC!

Melting point: 169.8°-170.8° C. (recrystallized from ethylacetate-isopropyl ether)

EXAMPLE 1331,2-Dihydro-N-(4-methoxybenzyl)-N,2,6,7-tetramethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamideC!

Melting point: 201°-202° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 134N-(4-Chlorobenzyl)-1,2-dihydro-N,2,6,7-tetramethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamideC!

Melting point: 175°-176° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 135 N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide

Melting point: 92°-93° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 136 1,2-Dihydro-N-2-(2-methoxyphenyl)ethyl!-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide

Melting point: 214°-216° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 137 1,2-Dihydro-N- 2-(2-methoxyphenyl)ethyl!-N,2,6,7-tetramethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide C!

Melting point: 110°-111° C. (recrystallized from ethyl ether-hexane)

EXAMPLE 138 N-2-(3,4-Dimethoxyphenyl)ethyl!-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide

Melting point: 185°-187° C. (recrystallized from THF-isopropyl ether)

EXAMPLE 1396-Chloro-1,2-dihydro-N-(4-methoxybenzyl)-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamide

Melting point: 181°-183° C. (recrystallized from ethyl acetate)

EXAMPLE 1406-Chloro-1,2-dihydro-N-(4-methoxybenzyl)-N,2-dimethyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamideC!

Melting point: 159°-160.5° C. (recrystallized from ethyl acetate)

EXAMPLE 141N-Benzyl-6-chloro-1,2-dihydro-N,2-dimethyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamide

Melting point: 151°-153° C. (recrystallized from ethyl acetate)

EXAMPLE 1427-Chloro-1,2-dihydro-N-(4-methoxybenzyl)-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamide

Melting point: 204°-205.5° C. (recrystallized from ethyl acetate)

EXAMPLE 143N-Benzyl-7-chloro-1,2-dihydro-N,2-dimethyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamide

Melting point: 171°-172° C. (recrystallized from ethyl acetate)

EXAMPLE 144 6-Chloro-1,2-dihydro-N-(2-methoxybenzyl)-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamide

Melting point: 200.5-202.5° C. (recrystallized from ethyl acetate)

EXAMPLE 1457-Chloro-1,2-dihydro-N-(2-methoxybenzyl)-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamide

Melting point: 187°-188° C. (recrystallized from ethyl acetate)

EXAMPLE 146N-Benzyl-1,2-dihydro-N,2,6,7-tetramethyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamide

Melting point: 177°-178° C. (recrystallized from ethyl acetate)

EXAMPLE 147N-Benzyl-1,2-dihydro-4-(2,6-dimethylphenyl)-N,2,6,7-tetramethyl-1-oxo-3-isoquinolinecarboxamide

Melting point: 186°-187.5° C. (recrystallized from ethyl acetate)

EXAMPLE 1481,2-Dihydro-N-furfuryl-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide

Melting point: 224°-225° C. (recrystallized from THF-isopropyl ether)

EXAMPLE 1491,2-Dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-N-(2-pyridyl)methyl-3-isoquinolinecarboxamide

Melting point: 218°-220° C. (recrystallized from THF-ethyl ether)

EXAMPLE 1501,2-Dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-N-(2-thienyl)methyl-3-isoquinolinecarboxamide

Melting point: 256.5°-258.0° C. (recrystallized fromtetrahydrofuran-isopropyl ether)

EXAMPLE 1511,2-Dihydro-N-(4-methoxybenzyl)-N,2-dimethyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamideC!

Melting point: 147°-150° C. (recrystallized from hexane-ethyl acetate)

EXAMPLE 152 1,2-Dihydro-N-2-(2-methoxyphenyl)ethyl!-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamide

Melting point: 217°-219° C. (recrystallized from ethyl acetate)

EXAMPLE 153 1,2-Dihydro-N-2-(2-methoxyphenyl)ethyl!-N,2-dimethyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamideC!

Melting point: 123°-125° C. (recrystallized from ethyl ether)

EXAMPLE 1541,2-dihydro-N-(2-methoxyphenyl)-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamide

Melting point: 142°-145° C. (recrystallized from ethyl ether)

EXAMPLE 1551,2-Dihydro-2-methyl-4-(2-methylphenyl)-1-oxo-N-(3,4,5-trimethoxyphenyl)-3-isoquinolinecarboxamide

Melting point: 222.5°-224° C. (recrystallized from ethyl acetate)

EXAMPLE 156 N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-2-methyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide

Melting point: 150°-152° C. (recrystallized from ethyl acetate-ethylether) NMR (200 MHz, CDCl₃) ppm: 3.55. (3H,s), 4.34 (2H, d, J=6.2 Hz),6.68 (1H, bt), 7.12-7.50 (8H, m), 7.52 (2H, s), 7.78 (1H, s), 8.37 (1H,m)

EXAMPLE 157 N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N,2-dimethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamideC!

Melting point: 144.5°-146° C. (recrystallized from ether) NMR (200 MHz,CDCl₃) ppm: 2.78 (3H,s), 3.61 (3H, s), 4.26 (1H, d, J=14.2 Hz), 4.75(2H, d, J=14.2 Hz), 7.19-7.40 (6H, m), 7.51 (2H, s), 7.53-7.58 (2H, m),7.81 (1H, s), 8.52 (1H, m)

EXAMPLE 158 N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-4-(2-methoxyphenyl)-2-methyl-1-oxo-3-isoquinolinecarboxamide

Melting point: 236°-238° C. (recrystallized from ethyl acetate)

EXAMPLE 159 N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-4-(2-methoxyphenyl)-N,2-dimethyl-1-oxo-3-isoquinolinecarboxamideC!

Melting point: 171°-173° C. (recrystallized from ethyl ethylacetate-ether)

EXAMPLE 1601,2-Dihydro-N-(2-methoxybenzyl)-4-(2-methoxyphenyl)-2-methyl-1-oxo-3-isoquinolinecarboxarnide

Melting point: 191°-193° C. (recrystallized from ethyl acetate)

EXAMPLE 1611,2-Dihydro-N-(2-methoxybenzyl)-4-(2-methoxyphenyl)-N,2-dimethyl-1-oxo-3-isoquinolinecarboxamideC!

Melting point: 146°-148.5° C. (recrystallized from ethyl acetate-ethylether)

EXAMPLE 162N-Benzyl-4-(2-ethylphenyl)-1,2-dihydro-N,2-dimethyl-1-oxo-3-isoquinolinecarboxamideC!

A colorless oily substance

NMR (200 MHz, CDCl₃) ppm: 1.04 (3H, t, J=7.6 Hz), 2.63 (2H, m), 2.83(3H, s), 3.61 (3H, s), 3.94 (1H, d, J=14.2 Hz), 5.06 (1H, d, J=14.2 Hz),6.60-6.65 (2H, m), 6.95-7.55 (10H, m), 8.52 (1H, m)

EXAMPLE 1634-(2-Ethylphenyl)-1,2-dihydro-N-(4-methoxybenzyl)-N,2-dimethyl-1-oxo-3-isoquinolinecarboxamideC!

A colorless oily substance

NMR (200 MHz, CDCl₃) ppm: 1.04 (3H, t, J=7.6 Hz), 2.66 (2H, m), 2.80(3H, s), 3.59 (3H, s), 3.80 (3H, s), 3.91 (1H, d, J=14.4 Hz), 4.94 (1H,d, J=14.4 Hz), 6.57-6.72 (4H, m), 6.94-7.19 (3H, m), 7.36-7.55 (4H, m),8.51 (1H, m)

EXAMPLE 164N-Benzyl-4-(2-ethylphenyl)-1,2-dihydro-N,2,6,7-tetramethyl-1-oxo-3-isoquinolinecarboxamide

A white powder

NMR (200 MHz, CDCl₃) ppm: 1.26 (3H, t, J=7.0 Hz), 2.23 (3H, s), 2.39(3H, s), 2.65 (2H, m), 2.73 (3H, s), 3.57 (3H, s), 3.79 (1H, d, J=14.0Hz), 4.92 (1H, d, J=14.0 Hz), 6.50-7.40 (10H, m), 8.26 (1H, s)

EXAMPLE 165 N-3,5-Bis(trifluoromethyl)benzyl!-4-(4-fluorophenyl)-1,2-dihydro-2-methyl-1-oxo-3-isoquinolinecarboxamide

Melting point: 184°-186° C. (recrystallized from ethyl ether) NMR (200MHz, CDCl₃) ppm: 3.59 (3H,s), 4.39 (2H, d, J=5.8 Hz), 6.32 (1H, bt, NH),6.95 (1H, t, J=8.4 Hz), 7.10-7.37 (5H, m), 7.51 (1H, m), 7.56 (2H, s),7.83 (1H, s), 8.45 (1H, m)

EXAMPLE 166 N-3,5-Bis(trifluoromethyl)benzyl!-4-(4-fluorophenyl)-1,2-dihydro-N,2-dimethyl-1-oxo-3-isoquinolinecarboxamide(C)

Melting point: 99°-101° C. (recrystallized from isopropyl ether-hexane)NMR (200 MHz, CDCl₃) ppm: 2.83 (3H, s), 3.60 (3H, s), 4.28 (1H, d,J=14.4 Hz), 4.78 (1H, d, J=14.4 Hz), 6.93-7.02 (2H, m), 7.13-7.39 (3H,m), 7.52-7.61 (4H, m), 7.84 (1H, s), 8.52 (1H, m)

EXAMPLE 1671,2-Dihydro-2-methyl-4-(2-methylphenyl)-1-oxo-N-(3,4,5-trimethoxybenzyl)-3-isoquinolinecarboxamide

Melting point: 227°-228° C. (recrystallized from ethyl acetate)

EXAMPLE 1681,2-Dihydro-N,2-dimethyl-4-(2-methylphenyl)-1-oxo-N-(3,4,5-trimethoxybenzyI)-3-isoquinolinecarboxamide(C)

Melting point: 178°-179.5° C. (recrystallized from ethyl acetate)

EXAMPLE 1691,2-Dihydro-2-methyl-N-(4-methylbenzyl)-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamide

Melting point: 165°-166° C. (recrystallized from ethyl acetate-ethylether)

EXAMPLE 1701,2-Dihydro-2-methyl-N-(4-methylbenzyl)-1-oxo-4-phenyl-3-isoquinolinecarboxamide

Melting point: 216°-217° C. (recrystallized from ethyl acetate-ethylether) NMR (200 MHz, CDCl₃) ppm: 2.32 (3H, s), 3.54 (3H, s), 4.19 (2H,d, J=5.4 Hz), 6.10 (1H, bt), 6.68 (2H, d, J=8.0 Hz), 7.02 (2H, d, J=8.0Hz), 7.20 (1H, d, J=7.8 Hz), 7.31-7.56 (7H, m), 8.37 (1H, dd, J=7.2, 1.0Hz)

EXAMPLE 171 1,2-Dihydro-2-methyl-1-oxo-4-phenyl-N-4-(trifluoromethyl)benzyl!-3-isoquinolinecarboxsmide

Melting point: 200°-201° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 3.51 (3H, s), 4.35 (2H, d, J=5,8 Hz),6.49 (1H, bt), 6.87 (2H, d, J=8.0 Hz), 7.16 (1H, d, J=8.0 Hz), 7.30-7.56(9H, m), 8.36 (1H, dd, J=7.9, 1.7 Hz)

EXAMPLE 172 N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N-methyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide

Melting point: 224°-225° C. (recrystallized from ethyl acetate-hexane)NMR (200 MHz, CDCl₃) ppm: 2.73 (3H, s), 7.20-7.70 (11H, m), 7.80 (1H,s), 8.53 (1H, d, J=8.4 Hz)

EXAMPLE 173 N-3,5-Bis(trifluoromethyl)benzyl!-6-chloro-1,2-dihydro-2-methyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide

Melting point: 164°-165° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 3.55 (3H, s), 4.34 (2H, d, J=6.0 Hz),6.54 (1H, b), 7.08 (1H, m), 7.20-7.95 (6H, m), 7.52 (2H, s), 7.80 (2H,s), 8.28 (1H, d, J=8.6 Hz)

EXAMPLE 174 N-3,5-Bis(trifluoromethyl)benzyl!-6-chloro-1,2-dihydro-N,2-dimethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide

Melting point: 165°-166° C. (recrystallized from ethyl acetate-ethylether) NMR (200 MHz, CDCl₃) ppm: 2.77 (3H, s), 3.59 (3H, s), 4.25 (1H,d, J=14.6 Hz), 4.74 (1H, d, J=14.6 Hz), 7.10-7.60 (9H, m), 7.80 (1H, s),8.44 (1H, d, J=8.0 Hz)

EXAMPLE 175 N-3,5-Bis(trifluoromethyl)benzyl!-4-(4-fluoro-2-methylphenyl)-1,2-dihydro-2-methyl-1-oxo-3-isoquinolinecarboxamide

Melting point: 189°-190° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.02 (3H, s), 3.41 (3H, s), 4.33 (1H,dd, J=15.0, 5.4 Hz), 4.50 (1H, dd, J=15.0, 5.4 Hz), 6.65-6.95 (4H, m),7.12 (1H, dd, J=8.4 Hz, 5.4 Hz), 7.48 (2H, m), 7.84 (1H, s), 8.34 (1H,d, J=7.6 Hz)

EXAMPLE 176 N-3,5-Bis(trifluoromethyl)benzyl!-4-(4-fluoro-2-methylphenyl)-1,2-dihydro-N,2-dimethyl-1-oxo-3-isoquinolinecarboxamide

Melting point: 142°-143° C. (recrystallized from ethyl acetate-ethylether) NMR (200 MHz, CDCl₃) ppm: 2.11 (3H, s), 2.99 (3H, s), 3.58 (3H,s), 4.11 (1H, d, J=14.7 Hz), 4.97 (1H, d, J=14.7 Hz), 6.65 (1H, m),6.80-7.63 (7H, m), 7.83 (1H, s), 8.51 (1H, m)

EXAMPLE 177 N-3,5-Bis(trifluoromethyl)benzyl!-6-chloro-1,2-dihydro-N-methyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide

Melting point: 251°-253° C. (recrystallized from ethyl acetate-hexane)NMR (200 MHz, CDCl₃) ppm: 2.73 (3H, s), 4.0-5.0 (2H, b), 7.33-7.56 (9H,m), 7.81 (1H, s), 8.35 (1H, d, J=8.4 Hz)

EXAMPLE 178 N-3,5-Bis(trifluoromethyl)benzyl!-4-(4-fluorophenyl)-1,2-dihydro-N-methyl-1-oxo-3-isoquinolinecarboxamide

Melting point: 225°-226° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.81 (3H, s), 4.1-5.1 (2H, b),6.99-7.80 (9H, m), 7.83 (1H, s), 8.46 (1H, d, J=7.4 Hz)

EXAMPLE 179 N-3,5-Bis(trifluoromethyl)benzyl!-2-(2-ethoxycarbonylethyl)-1,2-dihydro-1-oxo-4-phenyl-3-isoquinolinecarboxamide

Melting point: 155°-156° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 180 N-3,5-Bis(trifluoromethyl)benzyl!-2-(2-ethoxycarbonylethyl)-1,2-dihydro-N-methyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide

A white powder

NMR (200 MHz, CDCl₃) ppm: 1.26 (3H, t, J=7.0 Hz), 2.80 (3H, s), 2.97(2H, t, J=7.2 Hz), 3.83 (1H, m), 4.00-4.27 (3H, m), 4.68 (1H, m), 4.48(1H, d, J=14.2 Hz), 7.05-7.65 (10H, m), 7.80 (1H, s), 8.50 (1H, m)

EXAMPLE 181 N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-2-methyl-1-oxo-4-(2-trifluoromethylphenyl)-3-isoquinolinecarboxamide

Melting point: 176.5°-177.5° C. (recrystallized from ethyl acetate-ethylether)

EXAMPLE 182 N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N,2-dimethyl-1-oxo-4-(2-trifluoromethylphenyl)-3-isoquinolinecarboxamide(C)

Melting point: 159°-160° C. (recrystaIlized from ethyl acetate-ethylether) NMR (200 MHz, CDCl₃) ppm: 2.89 (3H, s), 3.58 (3H, s), 4.11 (1H,d, J=14.6 Hz), 4.98 (1H, d, J=14.6 Hz), 6.86 (1H, m), 7.43 (2H, s),7.46-7,56 (5H, m), 7.65 (1H, d, J=7.8 Hz), 7.78 (1H, s), 8.50 (1H, m)

EXAMPLE 183 N- 3,5-Bis(trifluoromethyl)benzyl!-2-2-(N,N-dimethylamino)ethyl!-1,2-dihydro-1-oxo-4-phenyl-3-isoquinolinecarboxamide

Melting point: 148°-149° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 184 N- 3,5-Bis(trifluoromethyl)benzyl!-2-2-(N,N-dimethylamino)ethyl!-1,2-dihydro-N-methyl-1-oxo-4-phenyl-3-isoquinolinecarboxamidehydrochloride

Melting point: 167°-168° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.87 (3H, s), 2.92 (3H, s), 3.04 (3H,s), 3.23-3.52 (1H, b), 3.62-3.85 (1H, b), 3.99 (1H, d, J=16.0 Hz),4.30-4.60 (1H, b), 4.75-5.00 (1H, b), 5.66 (1H, d, J=16.0 Hz), 7.08-7.35(6H, m), 7.42 (2H, s), 7.58 (2H, m), 7.77 (1H, s), 8.45 (1H, m)

EXAMPLE 185 N-3,5-Bis(trifluoromethyl)benzyl!-1,2,5,6,7,8-hexahydro-2-methyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide

Melting point: 224°-225° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 186 N-3,5-Bis(trifluoromethyl)benzyl!-1,2,5,6,7,8-hexahydro-N,2-dimethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide

Melting point: 200°-201° C. (recrystallized from ethyl acetate-hexane)NMR (200 MHz, CDCl₃) ppm: 1.40-2.70 (8H, m), 2.74 (3H, s), 3.50 (3H, s),4.17 (1H, d, J=14.6 Hz), 4.73 (1H, d, J=14.4 Hz), 7.04 (1H, m), 7.22(5H, m), 7.46 (2H, s), 7.78 (1H, m)

EXAMPLE 187 N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N-ethyl-2-methyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide(C)

Melting point: 99°-100° C. (recrystallized from ethyl acetate-hexane)NMR (200 MHz, CDCl₃) ppm: 1.02 (3H, t, J=7.2 Hz), 2.95 (1H, m), 3.45(1H, m), 3.61 (3H, s), 4.20 (1H, d, J=14.7 Hz), 4.87 (1H, d, J=14.7 Hz),7.2-7.6 (10H, m), 7.78 (1H, s), 8.49-8.54 (1H, m)

EXAMPLE 188 N-3,5-Bis(trifluoromethyl)benzyl!-5-fluoro-4-(4-fluorophenyl)-N,2-dimethyl-1-oxo-3-isoquinolinecarboxamide

Melting point: 96°-98° C. (recrystallized from isopropyl ether-ethylacetate) NMR (200 MHz, CDCl₃) ppm: 2.83 (3H, s), 3.57 (3H, s), 4.26 (1H,d, J=14.0 Hz), 4.67 (1H, d, J=14.6 Hz), 6.80-6.96 (2H, m), 7.06-7.40(2H, m), 7.42-7.54 (1H, m), 7.56 (2H, s), 7.83 (1H, d, J=1.2 Hz), 8.35(1H, dd, J=1.0, 8.0 Hz)

EXAMPLE 189 N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-2-ethyl-N-methyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide

The compound obtained in Example 172 was reacted with ethyl iodide by amethod similar to Example 102(C) to yield the title compound.

Melting point: 105°-106° C. (recrystallized from ethyl acetate-hexane)NMR (200 MHz, CDCl₃) ppm: 1.39 (3H, t, J=7.0 Hz), 2.75 (3H, s), 3.85(1H, m), 4.32 (1H, m), 4.45 (2H, s), 7.2-7.6 (10H, m), 7.80 (1H, s),8.49-8.54 (1H, m)

EXAMPLE 1901,2-Dihydro-N-(2-methoxybenzyl)-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinemethylamine

To a solution of the compound (300 mg) obtained in Reference Example 52in THF (5 ml) was added 2-methoxybenzylamine (0.51 ml), followed byheating at 130° C. in a sealed tube for 2 hours. After ethyl acetate wasadded, the reaction mixture was washed by successively with of aqueouspotassium carbonate and aqueous sodinrn chloride and then dried, afterwhich the solvent was distilled off. The residue was subjected to columnchromatography using silica gel (hexane:ethyl acetate=1:1) to yield thetitle compound as colorless crystals (301 mg).

Melting point: 159°-160° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.20 (3H, s), 2.36 (3H, s), 3.46 (2H,s), 3.64 (2H, s), 3.79 (3H, s), 3.82 (3H, s), 6.69 (1H, s), 6.80 (1H, d,J=7.8 Hz) 6.84 (1H, d, J=6.0 Hz), 7.03 (1H, d, J=6.0 Hz), 7.12-7.30 (3H,m), 7.35-7.50 (3H, m), 8.22 (1H, s)

Elemental analysis (for C₂₇ H₂₈ N₂ O₂):

Calculated: C, 78.61; H, 6.84; N, 6.79

Found: C, 78.47; H, 6.88; N, 6.69

1(2H)-Isoquinoline derivatives having respective correspondingsubstituents were reacted with amines in the same manner as in Example190 to yield the compounds of Example 191 to 206.

EXAMPLE 191N-(3,5-Dimethylbenzyl)-1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinemethylamine

Melting point: 129°-130° C. (recrystallized from ethyl ether-hexane) NMR(200 MHz, CDCl₃) ppm: 2.21 (3H, s), 2.27 (6H, s), 2.37 (3H, s), 3.48(2H, s), 3.56 (2H, s), 3.82 (3H, s), 6.70 (1H, s), 6.79 (2H, s), 6.86(1H, s), 7.15-7.30 (2H, m), 7.40-7.50 (3H, m), 8.24 (1H, s)

Elemental analysis (for C₂₈ H₃₀ N₂ O):

Calculated: C, 81.91; H, 7.37; N, 6.82

Found: C, 82.05; H, 7.37; N, 6.82

EXAMPLE 192N-(2-Chlorobenzyl)-1,2-dihydro-N,2,6,7-tetramethyl-1-oxo-4-phenyl-3-isoquinolinemethylamine

Melting point: 117°-118° C. (recrystallized from ethyl ether-hexane)

EXAMPLE 193N-(2-Chlorobenzyl)-1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinemethylamine

Melting point: 141°-142° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 194 1,2-Dihydro-N-2-(2-methoxyphenyl)ethyl!-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinemethylamine

Melting point: 119°-120° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 195 N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinemethylaminehydrochloride

A white powder

NMR (200 MHz, DMSO-d₆) ppm: 2.19 (3H, s), 2.36 (3H, s), 3.74 (3H, s),4.05 (2H, bs), 4.14 (2H, bs), 6.63 (1H, s), 7.30-7.50 (5H, m), 8.12 (4H,s), 9.94 (2H, bs)

Elemental analysis (for C₂₈ H₂₅ N₂ OClF₆):

Calculated: C, 60.60; H, 4.54; N, 5.05

Found: C, 60.78; H, 4.63; N, 4.78

EXAMPLE 1961,2-Dihydro-N-(2-methoxybenzyl)-N,2,6,7-tetramethyl-1-oxo-4-phenyl-3-isoquinolinemethylamine

Melting point: 91°-92° C. (recrystallized from ethyl ether-hexane)

EXAMPLE 1971,2-Dihydro-N-(2-methoxybenzyl)-2-methyl-1-oxo-4-phenyl-3-isoquirxolinemethylamine

Melting point: 212°-214° C. (recrystallized from ethyl ethylacetate-ether)

EXAMPLE 1981,2-Dihydro-N-(3-methoxybenzyl)-2-methyl-1-oxo-4-phenyl-3-isoquinolinemethylamine

Melting point: 95°-96° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 1991,2-Dihydro-N-(4-methoxybenzyl)-2-methyl-1-oxo-4-phenyl-3-isoquinolinemethylamide

Melting point: 94°-95° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 200 N-3,5-Bis(trifluoromethyl)phenyl!-1,2-dihydro-2-methyl-1-oxo-4-phenyl-3-isoquinolinemethylamine

Melting point: 241°-242° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 201 N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N,2-dimethyl-1-oxo-4-phenyl-3-isoquinolinemethylamine

Melting point: 135°-136° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 2021,2-Dihydro-2-methyl-1-oxo-4-phenyl-N-(2-pyridyl)methyl-3-isoquinolinemethylamine

Melting point: 145°-146° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 2031,2-Dihydro-N-(2-methoxybenzyl)-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinemethylamine

Melting point: 91°-92° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 204 N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinemethylaminehydrochloride

A white powder

NMR (200 MHz, DMSO-d₆) ppm: 1.95 (3H, s), 3.77 (3H, s), 3.50-4.50 (4H,m), 6.70-6.85 (1H, m), 7.20-7.45 (4H, m), 7.50-7.70 (2H, m), 8.07 (3H,s), 8.30-8.40 (1H, m), 9.60-10.60 (1H, m)

EXAMPLE 2051,2-Dihydro-2-methyl-1-oxo-4-phenyl-N-(3,4,5-trimethoxybenzyl)-3-isoquinolinemethylamine

Melting point: 131°-132° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 3.54 (2H, s), 3.59 (2H, s), 3.82 (9H,s), 3.86 (3H, s), 6.45 (2H, s), 6.96 (1H, m), 7.20-7.28 (2H, m),7.42-7.50 (5H, m), 8.49 (1H, m)

EXAMPLE 2064-(2-Ethylphenyl)-1,2-dihydro-N-(2-methoxybenzyl)-2-methyl-1-oxo-3-isoquinolinemethylaminehydrochloride

A white powder

NMR (200 MHz, CDCl₃) ppm: 0.98 (3H; t, J=7.5 Hz), 2.30 (2H, q, J=7.5Hz), 3.40 (1H, d, J=13Hz), 3.49 (1H, d, J=13 Hz), 3.65 (2H, s), 3.78(3H, s), 3.85 (3H, s), 6.73-6.88 (3H, m), 7.00-7.29 (4H, m), 7.33-7.48(4H, m), 8.48 (1H, m)

EXAMPLE 2071,2-Dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinemethyl2-(2-methoxyphenyl)ethyl ether

A mixture of 2-methoxyphenethyl alcohol (0.125 ml), sodium hydride (60%in oil) (50 mg) and DMF (5 ml) was stirred at room temperature for 30minutes. After this mixture was cooled to 0° C., the compound (200 mg)obtained in Reference Example 52 was added, followed by stirring at roomtemperature for 30 minutes. After dilute hydrochloric acid was added,the mixture was extracted with ethyl acetate. The extract was washedwith aqueous potassium carbonate and water and then dried, after whichthe solvent was distilled off. The residue was subjected to columnchromatography using silica gel (hexane:ethyl acetate=3:2) to yield thetitle compound as colorless crystals (101 mg).

Melting point: 114°-115° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.22 (3H, s), 2.38 (3H, s), 2.83 (2H,t, J=7.0 Hz), 3.53 (2H, t, J=7.0 Hz), 3.67 (3H, s), 3.76 (3H, s), 4.22(2H, s), 6.78-6.92 (3H, m), 7.05-7.30 (4H, m), 7.38-7.50 (3H, m), 8.25(1H, s)

Elemental analysis (for C₂₈ H₂₉ NO₃):

Calculated: C, 78.66; H, 6.84; N, 3.28

Found: C, 78.60; H, 6.91; N, 3.19

1(2H)-Isoquinolinone derivatives having respective correspondingsubstituents were reacted with alcohols in the same manner as in Example207 to yield the compounds of Examples 208 to 216.

EXAMPLE 2081,2-Dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinemethyl3,5-dimethylbenzyl ether

Melting point: 99°-100° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.23 (3H, s), 2.28 (6H, s), 2.38 (3H,s), 3.78 (3H, s), 4.28 (2H, s), 4.30 (2H, s), 6.81 (1H, s), 6.84 (2H,s), 6.91 (1H, s), 7.25-7.35 (2H, m), 7.40-7.50 (3H, m), 8.26 (1H, s)

Elemental analysis (for C₂₈ H₂₉ NO₂):

Calculated: C, 81.72; H, 7.10; N; 3.40

Found: C, 81.64; H, 7.29; N, 3.25

EXAMPLE 209 Benzyl1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinoline-methyl ether

Melting point: 127°-128° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 2101,2-Dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinemethyl2-methoxybenzyl ether

Melting point: 105°-106° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 211 3,5-Bis(trifluoromethyl)benzyl1,2-dihydro-2-methyl-1-oxo-4-phenyl-3-isoquinolinemethyl ether

Melting point: 133°-134° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 3.83 (3H, s), 4.42 (2H, s), 4.48 (2H,s), 7.00-7.10 (1H, m), 7.20-7.30 (2H, m), 7.35-7.60 (5H, m), 7.67 (2H,s), 7.79 (1H, s), 8.45-8.60 (1H, m)

EXAMPLE 212 3,5-Bis(trifluoromethyl)benzyl1,2-dihydro-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquinoline methylether

A colorless oily substance

NMR (200 MHz, CDCl₃) ppm: 2.02 (3H, s), 3.85 (3H, s), 4.28 (1H, d, J=12Hz), 4.45 (1H, d, J=12 Hz), 4.48 (2H, s), 6.85-7.00 (1H, m), 7.10-7.35(4H, m), 7.45-7.55 (2H, m), 7.66 (2H, s), 7.79 (1H, s), 8.50-8.60 (1H,m)

EXAMPLE 213 1,2-Dihydro-2-methyl-1-oxo-4-phenyl-3-isoquinolinemethyl2-(2-methoxyphenyl)ethyl ether

Melting point: 145°-147° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.83 (2H, t, J=6.8 Hz), 3.54 (2H, t,J=6.8 Hz), 3.68 (3H, s), 3.75 (3H, s), 4.25 (2H, s), 6.78-6.92 (2H, m),7.04-7.30 (5H, m), 7.38-7.52 (5H, m), 8.46-8.54 (1H, m)

EXAMPLE 2141,2-Dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinemethyl4-methoxybenzyl ether

Melting point: 123°-124° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 2152-(1,2-Dihydro-2,6,7-trimethyl-1-oxo-4-phenylisoquinoline-3-yl)ethyl-3,5-dimethylbenzylether

Melting point: 150°-151° C. (recrystallized from ethylether-hexane)

EXAMPLE 216 3,5-Bis(trifluoromethyl)benzyl4-(2-ethylphenyl)-1,2-dihydro-2-methyl-1-oxo-3-isoquinolinemethyl ether

A colorless oil

NMR (200 MHz, CDCl₃) ppm: 0.99 (3H, t, J=7.7 Hz), 2.34 (2H, q, J=7.7Hz), 3.82 (3H, s), 4.27 (1H, d, J=12 Hz), 4.45 (1H, d, J=12 Hz), 4.48(2H, s), 6.93 (1H, m), 7.10-7.57 (6H, m), 7.67 (2H, s), 7.79 (1H, s),8.51 (1H, m)

EXAMPLE 217 3,5-Bis(trifluoromethyl)benzyl1,2-dihydro-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinemethylsulfide

The compound obtained in Reference Example 68 was reacted with3,5-bis(trifluoromethyl)benzyl bromide in DMF in the presence of sodintohydride by a method similar to Example 207 to yield the title compoundas colorless crystals.

Melting point: 178°-179° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 218 3,5-Bis(trifluoromethyl)benzyl1,2-dihydro-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinemethylsulfoxide

A mixture of the compound obtained in Reference Example 217,m-chloroperbenzoic acid (purity 70%) (50 mg) and dichloromethane (20 ml)was stirred for 30 minutes with ice cooling. After evaporation of thesolvent, the residue was dissolved in ethyl acetate, washed successivelywith water, diluted hydrochloric acid and aqueous sodium hydrogencarbonate, dried and evaporated. The residue was subjected to silica gelcolumn chromatography (ethyl acetate) to yield the title compound ascolorless crystals (60.3 mg).

Melting point: 173°-174° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.97, 2.00 (total 3H, each s),3.65-3.95 (4H, m), 3.80, 3.81 (total 3H, each s), 6.83 (1H, m), 7.10(1H, m), 7.19-7.35 (3H, m), 7.45-7.55 (4H, m), 7.84 (1H, s), 8.50 (1H,m)

EXAMPLE 219N-Benzyl-1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolineacetamide

1,2-Dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolineacetic acid(Reference Example 56) and benzylamine were reacted (amidation) andtreated in substantially the same manner as in Example 101 to yield thetitle compound as colorless crystals.

Melting point: 222-222.5° C. (recrystallized from ethylacetate-isopropyl ether) NMR (200 MHz, CDCl₃) ppm: 2.19 (3H, s), 2.34(3H, s), 3.54 (2H, s), 3.66 (3H, s), 4.41 (2H, d, J=6.0 Hz), 5.87 (1H,bt), 6.68 (1H, s), 7.10-7.45 (10H, m), 8.18 (1H, s)

Elemental analysis (for C₂₇ H₂₆ N₂ O₂ ·0.1H₂ O):

Calculated: C, 78.65; H, 6.40; N, 6.79

Found: C, 78.46; H, 6.40; N, 6.94

Isoquinolineacetic acid derivatives having respective correspondingsubstituents were reacted with amines in the same manner as in Example219 to yield the compounds of Example 220 to 223.

EXAMPLE 2201,2-Dihydro-N-(4-methoxybenzyl)-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolineacetamide

Melting point: 214°-215° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 221N-(2-Chlorobenzyl)-1,2-dihydro-N,2,6,7-tetramethyl-1-oxo-4-phenyl-3-isoquinolineacetamide

Melting point: 191°-192° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 222 N-3,5-Bis(trifluoromethyl)benzyl!-6-chloro-1,2-dihydro-N,2-dimethyl-1-oxo-4-phenyl-3-isoquinolineacetamide

Melting point: 156°-157° C. (recrystallized from ethyl acetate-hexane)

EXAMPLE 223 N-3,5-Bis(trifluoromethyl)phenyl!-6-chloro-1,2-dihydro-2-methyl-1-oxo-4-phenyl-3-isoquinolineacetamide

Melting point: 288°-289° C. (recrystallized from methanol-ethyl acetate)

EXAMPLE 224 N- 3,5-Bis(trifluoromethyl)phenyl!-1,2-dihydro-N,2-dimethyl-1-oxo-4-phenyl-3-isoquinolineacetamide

A mixture of the compound obtained in Example 222 (250 mg), methanol (8ml), THF (2 ml), 10% palladium-carbon (50% hydrated) (130 mg) and sodiumacetate (60 mg) was stirred in a hydrogen atmosphere for 1 hour at roomtemperature. The catalyst was filtered off, and the filtrate wasevaporated. The residue was dissolved in ethyl acetate, washed withwater, dried and evaporated to yield the title compound as colorlesscrystals (160 mg).

Melting point: 193°-194° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 225 N-3,5-Bis(trifluoromethyl)benzyl!-2-carbamoylmethyl-1,2-dihydro-6,7-dimethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide

To a solution of the compound (190 mg) obtained in Reference Example 59in dichloromethane (10 ml) were added oxalyl chloride (0.052 ml) and DMF(one drop), followed by stirring at room temperature for 1 hour. Afterthe solvent was distilled off, the residue was dissolved indichloromethane (10 ml). To this solution was added a solution of3,5-bis(trifluoromethyl)benzylamine (170 mg) and triethylamine (0.077ml) in dichloromethane (5 ml), followed by stirring at room temperaturefor 5 hours. After the solvent was distilled off, ethyl acetate wasadded to the residue. This mixture was washed successively with water,dilute hydrochloric acid, water, aqueous sodium hydrogen carbonate andwater and then dried, after which the solvent was distilled off. Theresidue was dissolved in methanol (5 ml), and 15% ammonia-methanol (10ml) was added at room temperature, followed by stirring for 15 hours andthen solvent removal by distillation, to yield the title compound ascolorless crystals (125 mg).

Melting point: 235°-237° C. (recrystallized from methanol)

Elemental analysis (for C₂₉ H₂₃ N₃ O₃ F₆):

Calculated: C, 60.52; H, 4.03; N, 7.30

Found: C, 60.72; H, 4.11; N, 7.52

The compound obtained in Reference Example 59 and benzylamines havingrespective corresponding substituents were reacted and treated in thesame manner as in Example 225 to yield the compounds of Examples 226 and227.

EXAMPLE 2262-Carbamoylmethyl-1,2-dihydro-6,7-dimethyl-N-(3,5-dimethylbenzyl)-1-oxo-4-phenyl-3-isoquinolinecarboxamide

Melting point: 253°-254° C. (recrystallized from ethanol)

EXAMPLE 2272-Carbamoylmethyl-1,2-dihydro-N-(2-methoxybenzyl)-6,7-dimethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide

Melting point: 234.5°-236° C. (recrystallized from ethanol)

EXAMPLE 2281,2,3,4-Tetrahydro-2-(2-methoxybenzyl)-8,9-dimethyl-3,6-dioxo-11-phenyl-6H-pyrazino1,2-b!isoquinoline

To a solution of2-ethoxycarbonylmethyl-1,2-dihydro-3-hydroxymethyl-6,7-dimethyl-1-oxo-4-phenylisoquinoline(Reference Example 51) (183 mg) in dichloromethane (10 ml) were addedmethanesulfonyl chloride (0.037 ml) and triethylamine (0.084 ml) withice cooling, followed by stirring for 30 minutes. The reaction mixturewas poured into water and extracted with dichloromethane. The extractwas washed with water and then dried, after which the solvent wasdistilled off. The residue was mixed with 2-methoxybenzylamine (0.196ml) and THF (5 ml), followed by heating at 130° C. in a sealed tube for3 hours. The reaction mixture was poured into aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed withwater and then dried, after which the solvent was distilled off. Theresidue was subjected to silica gel column chromatography(hexane:acetone=1:1) to yield the title compound as colorless crystals(110 mg).

Melting point: 211°-214° C. (recrystallized from ethyl acetate-hexane)NMR (200 MHz, CDCl₃) ppm: 2.22 (3H, s), 2.37 (3H, s), 3.54 (3H, s), 4.15(2H, s), 4.60 (2H, s), 4.88 (2H, s), 6.76-6.98 (5H, m), 7.13-7.28 (2H,m), 7.36-7.42 (3H, m), 8.23 (1H, s)

Elemental analysis (for C₂₈ H₂₆ N₂ O₃):

Calculated: C, 76.67; H, 5.97; N, 6.39

Found: C, 76.41; H, 6.05; N, 6.40

EXAMPLE 2291,2,3,4-Tetrahydro-1-(4-methoxybenzyloxy)-8,9-dimethyl-6-oxo-11-phenyl-6H-benzob!quinolizine

To a solution of the compound (160 mg) obtained in Reference Example 65in DMF (5 ml) was added sodium hydride (60% in oil) (22 mg), followed bystirring at room temperature for 15 minutes. While ice cooling thesolution, 4-methoxybenzyl chloride (0.075 ml) was added, followed bystirring at room temperature for 4 hours. The reaction mixture waspoured into water and extracted with ethyl acetate. The extract waswashed successively with dilute hydrochloric acid, water, aqueous sodiumhydrogen carbonate and water and then dried, after which the solvent wasdistilled off. The residue was subjected to silica gel columnchromatography (hexane:ethyl acetate=5:1) to yield the title compound ascolorless crystals (170 mg).

Melting point: 145°-146° C. (recrystallized from ethyl ether-hexane)

Elemental analysis (for C₂₉ H₂₉ NO₃):

Calculated: C, 79.24; H, 6.65; N, 3.19

Found: C, 79.30; H, 6.85; N, 3.14

The compound obtained in Reference Example 65 and benzyl chlorideshaving respective corresponding substituents were reacted (alkylation)and treated in the same manner as in Example 229 to yield the compoundsof Examples 230 to 232

EXAMPLE 2301-Benzyloxy-1,2,3,4-tetrahydro-8,9-dimethyl-6-oxo-11-phenyl-6H-benzob!quinolizine

Melting point: 133°-134° C. (recrystallized from ethyl ether-hexane)

EXAMPLE 2311-(3,5-Dimethylbenzyloxy)-1,2,3,4-tetrahydro-8,9-dimethyl-6-oxo-11-phenyl-6H-benzob!quinolizine

Melting point: 146°-147° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 2321,2,3,4-Tetrahydro-1-(2-methoxybenzyloxy)-8,9-dimethyl-6-oxo-11-phenyl-6H-benzob!quinolizine

Melting point: 186°-188° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 2331-(3,5-Dimethylbenzylamino)-1,2,3,4-tetrahydro-8,9-dimethyl-6-oxo-11-phenyl-6H-benzob!quinolizine hydrochloride

A mixture of the compound (159 mg) obtained in Reference Example 64,acetic acid (0.03 ml), 3,5-dimethylbenzaldehyde (0.1 ml) and methanol(10 ml) was stirred at room temperature for 15 minutes. After sodiumcyanoborohydride (60 mg) was added, the mixture was stirred at roomtemperature for 30 minutes. After the solvent was distilled off, aqueoussodium hydrogen carbonate was added, and the mixture was extracted withethyl acetate. The extract was washed with water and then dried, afterwhich the solvent was distilled off, to yield the free form of the titlecompound as a colorless oily substance. This compound was dissolved inether (1 ml), and 4N HCl-ethyl acetate (3 ml) was added while icecooling the solution, followed by solvent removal by distillation, toyield the title compound as colorless crystals (160 mg).

Melting point: 205°-208° C. (recrystallized from ethanol) NMR (200 MHz,CDCl₃) ppm: free base!

1.55-2.05 (4H, m), 2.22 (3H, s), 2.25 (6H, s), 2.36 (3H, s), 3.20 (1H,d, J=12.4 Hz), 3.40 (1H, d, J=12.4 Hz), 3.91 (1H, bs), 4.30 (1H, m),4.59 (1H, m), 6.70 (2H, s), 6.74 (1H, s), 6.83 (1H, s), 7.21-7.32 (2H,m), 7.48 (3H, m), 8.24 (1H, s)

Elemental analysis (for C₃₀ H₃₂ N₂ O·HCl·0.2H₂ O):

Calculated: C, 75.59; H, 7.06; N, 5.88

Found: C, 75.42; H, 7.29; N, 5.72

EXAMPLE 234 1,2,3,4-Tetrahydro-8,9-dimethyl-1-N-methyl-(3,5-dimethylbenzyl)amino!-6-oxo-11-phenyl-6H-benzob!quinolizine

The compound obtained in Example 233 and formalin were reacted andtreated with sodium borohydride in the same manner as in Example 233 toyield the title compound as colorless crystals.

Melting point: 144°-145° C. (recrystallized from ethyl acetate-isopropylether)

Amine compounds having respective corresponding substituents andaldehydes were reacted and treated with sodium borohydride in the samemanner as in Examples 233 and 234 to yield the compounds of Example 235to 239 (free form or hydrochloride).

EXAMPLE 235 1-3,5-Bis(trifluoromethyl)benzylamino!-1,2,3,4-tetrahydro-8,9-dimethyl-6-oxo-11-phenyl-6H-benzob!quinolizine

Melting point: 189.5°-191.5° C. (recrystallized from isopropyl ether)NMR (200 MHz, CDCl₃) ppm: 1.70-2.00 (4H, m), 2.22 (3H, s), 2.38 (3H, s),3.36 (1H, d, J=13.4 Hz), 3.56 (1H, d, J=13.4 Hz), 3.94 (1H, bs), 4.27(1H, m), 4.56 (1H, m), 6.74 (1H, s), 7.25 (2H, m), 7.47 (3H, m), 7.57(2H, s), 7.71 (1H, s), 8.25 (1H, s)

Elemental analysis (for C₃₀ H₂₆ N₂ OF₆):

Calculated: C, 66.17; H, 4.81; N, 5.14

Found: C, 65.88; H, 4.79; N, 5.01

EXAMPLE 236 1,2,3,4-Tetrahydro-8,9-dimethyl-1- N-methyl-3,5-bis(trifluoromethyl) benzyl!amino!-6-oxo-11-phenyl-6H-benzob!quinolizine hydrochloride

Melting point: 116°-119° C. (recrystallized from ethanol)

EXAMPLE 2371-(2-Chlorobenzylamino)-1,2,3,4-tetrahydro-8,9-dimethyl-6-oxo-11-phenyl-6H-benzob!quinolizine hydrochloride

Melting point: 201°-204° C. (recrystallized From ethanol)

EXAMPLE 2381,2,8,4-Tetrahydro-1-(2-methoxybenzylamino)-8,9-dimethyl-6-oxo-11-phenyl-6H-benzob!quinolizine hydrochloride

Melting point: 211°-215° C. (recrystallized from methanol-ethanol)

EXAMPLE 2891,2,3,4-Tetrahydro-1-(2-methoxybenzylamino)-6-oxo-11-phenyl-6H-benzob!quinolizine

Melting point: 135°-137° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 240 N-3,5-Bis(trifluoromethyl)benzyl!-1,2,3,4-tetrahydro-1,6-dioxo-11-phenyl-6H-pyrazino1,2-b!isoquinoline

A solution of the compound obtained in Reference Example 66 (103 mg) inDMF (5 ml) was added sodium hydride (60% in oil) (16 mg), and themixture was stirred for 30 minutes at room temperature, followed byaddition of 3,5-bis(trifluoromethyl)benzyl bromide (74 μl) with icecooling and the mixture was stirred for 1 hour at room temperature.Water was added to the mixture, which was extracted with ethyl acetate.The extract was washed with water, dried and evaporated to yield thetitle compound as colorless crystals (65 mg).

Melting point: 204°-206° C. (recrystallized from ethyl acetate-ethylether) NMR (200 MHz, CDCl₃) ppm: 3.63 (2H, m), 4.44 (2H, m), 4.78 (2H,s), 7.18-7.27 (3H, m), 7.44-7.66 (5H, m), 7.68 (2H, s), 7.82 (2H, s),8.52 (1H, m)

EXAMPLE 241 N-3,5-Bis(trifluoromethyl)benzyl!-1,2,3,4-tetrahydro-1,6-dioxo-11-phenyl-6H-pyrazino1,2-b!isoquinoline

A solution of the compound obtained in Reference Example 67 (140 mg) inDMF (5 ml) were added potassium carbonate (76 mg) and3,5-bis(trifluoromethyl)benzyl bromide (111 μl), and the mixture wasstirred for 30 minutes at 70°-80° C. Water was added to the mixture,which was extracted with ethyl acetate. The extract was washed withwater, dried and evaporated to yield the title compound as colorlesscrystals (170 mg).

Melting point: 194°-196° C. (recrystallized from ethyl acetate)

EXAMPLE 242 N-3,5-Bis(trifluoromethyl)benzyl!-6-chloro-N-methyl-1-oxo-4-phenyl-1H-2-benzopyran-3-carboxamide

6-Chloro-1-oxo-4-phenyl-1H-2-benzopyran-3-carboxylic acid was reactedwith N- 3,5-bis(trifluoromethyl)benzyl!methylamine by a method similarto Example 101 (amidation) to yield the title compound.

Melting point: 170°-171° C. (recrystallized from ethyl acetate-hexane)NMR (200 MHz, CDCl₃) ppm: 2.78 (3/5H, s), 2.91 (3×4/5H, s), 4.59 (2H,s), 7.18 (1H, s), 7.27-7.57 (8H, m), 7.80 (1H, s), 8.33 (1H, d, J=8.6Hz)

The compounds of Example 243-247 were obtained from the1-oxo-1H-2-benzopyran-3-carboxylic acids and amines, which havesubstituents corresponding to each Example, by a method similar toExample 242 (amidation).

EXAMPLE 243 N-3,5-Bis(trifluoromethyl)benzyl!-N-methyl-1-oxo-4-phenyl-1H-2-benzopyran-3-carboxamide

Melting point: 151°-152° C. (recrystallized from ethyl acetate-hexane)NMR (200 MHz, CDCl₃) ppm: 2.78 (3/5H, s), 2.92 (3×4/5H, s), 4.60 (2H,s), 7.22-7.75 (10H, m), 7.80 (1H, s), 8.39-8.43 (1H, m)

EXAMPLE 244 N-3,5-Bis(trifluoromethyl)benzyl!-4-(2-methoxyphenyl)-N-methyl-1-oxo-1H-2-benzopyran-3-carboxamide

Melting point: 153°-154° C. (recrystallized from ethyl acetate-hexane)NMR (200 MHz, CDCl₃) ppm: 2.91 (3/4H, s), 3.06 (3×3/4H, s), 3.56 (3/4H,s), 3.74 (3×3/4H, s), 4.42 (1H, d, J=14.6 Hz), 5.01 (1H, d, J=14.6 Hz),6.95-7.80 (9H, m), 7.91 (1H, s), 8.48-8.53 (1H, m)

EXAMPLE 245 N-3,5-Bis(trifluoromethyl)benzyl!-4-(4-fluorophenyl)-1-oxo-1H-2-benzopyran-3-carboxamide

Melting point: 166°-167° C. (recrystallized from ethyl ether)

EXAMPLE 246 N-3,5-Bis(trifluoromethyl)benzyl!-4-(4-fluorophenyl)-N-methyl-1-oxo-1H-2-benzopyran-3-carboximide

Melting point: 132°-133° C. (recrystallized from ethyl ether-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.96 (3H, s), 4.61 (2H, s), 7.08 (1H,d, J=8.6 Hz), 7.13-7.22 (2H, m), 7.30 (1H, dd, J=7.2, 3.6 Hz), 7.32 (1H,m), 7.52 (2H, s), 7.58-7.76 (2H, m), 7.82 (1H, s), 8.41 (1H, dd, J=7.2,1.2 Hz)

EXAMPLE 247 N-3,5-Bis(trifluoromethyl)benzyl!-N,6-dimethyl-1-oxo-4-phenyl-1H-2-benzopyran-3-carboxmamide

Melting point: 162°-163° C. (recrystallized from isopropyl ether-hexane)NMR (200 MHz, CDCl₃) ppm: 2.38, 2.39 (total 3H, each s), 2.77 (1/4×3H,s), 2.91 (3/4×3H, s), 4.58 (2H, s), 6.99 (1H, s), 7.25-7.42 (6H, m),7.49 (2H, s), 7.78 (1H, s), 8.29 (1H, d, J=8.0 Hz)

EXAMPLE 248 N-3,5-Bis(trifluoromethyl)benzyl!-6-chloro-N-methyl-4-(2-methylphenyl)-2-oxo-4H-1-benzopyran-3-carboxamide

6-Chloro-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid wasreacted with N- 3,5-bis(trifluoromethyl)benzyl!methylamine by a methodsimilar to Example 101 (amidation) to yield the title compound.

Melting point: 148°-149° C. (recrystalized from ethyl acetate-hexane)NMR (200 MHz, CDCl₃) ppm: 2.08 (1H, s), 2.20 (2H, s), 2.86 (1H, s), 3.00(2H, s), 4.37 (1H, d, J=15.2 Hz), 4.88 (2/3H, d, J=15.2 Hz), 4.92 (1/3H,d, J=15.2 Hz), 6.89-7.56 (9H, m), 7.76 (1H, s)

The compounds of Example 249-253 were obtained from the2-oxo-2H-1-benzopyran-3-carboxylic acids and amines, which havesubstituents corresponding to each Example, by a method similar toExample 248 (amidation).

EXAMPLE 249 N-3,5-Bis(trifluoromethyl)benzyl!-6-chloro-N-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxamide

Melting point: 172°-173° C. (recrystalized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.74 (0.57H, s), 2.85 (2.43H, s), 4.18(0.19H, d, J=15.6 Hz), 4.40 (0.81H, d, J=15.4 Hz), 4.63 (0.19H, d,J=16.2 Hz), 4.88 (0.81H, d, J=15.0 Hz), 7.12-7.70 (10H, m), 7.78 (1H, s)

EXAMPLE 250 N-3,5-Bis(trifluoromethyl)benzyl!-N-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxamide

Melting point: 146°-147° C. (recrystallized from ethyl acetate hexane)NMR (200 MHz, CDCl₃) ppm: 2.74 (3/5H, s), 2.86 (3×4/5H, s), 4.22 (1/5H,d, J=15.6 Hz), 4.39 (4/5H, d, J=15.2 Hz), 4.69 (1/5H, d, J=15.6 Hz),4.91 (4/5H, d, J=15.2 Hz), 7.14-7.70 (11H, m), 7.78 (1H, s)

EXAMPLE 251 N-3,5-Bis(trifluoromethyl)benzyl!-6-chloro-4-(2-methoxyphenyl)-N-methyl-2-oxo-2H-1-benzopyran-3-carboxamide

Melting point: 121°-122° C. (recrystallized from isopropyl ether-ethylacetate) NMR (200 MHz, CDCl₃) ppm: 2.85 (3H, s), 3.63 (3H, s), 4.29 (1H,d, J=15.4 Hz), 4.98 (1H, d, J=15.0 Hz), 6.90-7.09 (3H, m), 7.30-7.64(6H, m), 7.77 (1H, s)

EXAMPLE 252 N-3,5-Bis(trifluoromethyl)benzyl!-6-chloro-N-methyl-2-oxo-4-(2-trifluoromethylphenyl)-2H-1-benzopyran-3-carboxamide

Melting point: 206°-207° C. (recrystallized from ethyl acetate) NMR (200MHz, CDCl₃) ppm: 2.92 (3H, s), 4.33 (1H, d, J=15.2 Hz), 4.92 (1H, d,J=15.4Hz), 6.77 (1H, d, J=2.2 Hz), 7.38 (1H, d, J=8.8 Hz), 7.46-7.58(3H, m), 7.60-7.88 (5H, m)

EXAMPLE 2536-Chloro-N-(2,6-dimethoxybenzyl)-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-carboxamide

Melting point: 190°-191° C. (recrystallized from ethanol)

EXAMPLE 254 N-3,5-Bis(trifluoromethyl)benzyl!-N-methyl-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-carboxamide

The compound obtained in Reference 248 was reacted by a method similarto Example 224 (catalytic reduction) to yield the title compound.

Melting point: 130°-13 1° C. (recrystallized from ethyl acetate-hexane)NMR (200 MHz, CDCl₃) ppm: 2.07 (1H, s), 2.22 (2H, s), 2.87 (1H, s), 3.01(2H, s), 4.36 (1H, d, J=15.2 Hz), 4.90 (2/3H, d, J=15.2 Hz), 4.95 (1/3H,d, J=15.2 Hz), 6.92-7.57 (10H, m), 7.76 (1H, s)

The compounds of Example 255 and 256 were obtained from the compounds ofExample 251 and 252, respectively, by a method similar to Example 254

EXAMPLE 255 N-3,5-Bis(trifluoromethyl)benzyl!-4-(2-methoxyphenyl)-N-methyl-2-oxo-2H-1-benzopyran-3-carboxamide

Melting point: 140°-142° C. (recrystallized from isopropyl ether-ethylacetate) NMR (200 MHz, CDCl₃) ppm: 2.87 (3H, s), 3.61 (3H, s), 4.28 (1H,d, J=15.2 Hz), 5.01 (1H, d, J=15.2 Hz), 6.85-7.22 (4H, m), 7.30-7.62(6H, m), 7.77 (1H, s)

EXAMPLE 256 N-3,5-Bis(trifluoromethyl)benzyl!-N-methyl-2-oxo-4-(2-trifluoromethylphenyl)-2H-1-benzopyran-3-carboxamide

Melting point: 135°-137° C. (recrystallized from isopropyl ether-ethylacetate) NMR (200 MHz, CDCl₃) ppm: 2.94 (3H, s), 4.33 (1H, d, J=15.4Hz), 4.95 (1H, d, J=15.0 Hz), 6.84 (1H, dd, J=1.4, 8.0 Hz), 7.20 (1H,dt, J=1.4, 7.2 Hz), 7.43 (1H, dd, J=1.0, 8.4 Hz), 7.52-7.82 (8H, m)

EXAMPLE 257 N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-2-oxo-4-phenyl-3-quinolinecarboxamide

1,2-Dihydro-2-oxo-4-phenyl-3-quinolinecarboxylic acid was reacted with3,5-bis(trifluoromethyl)benzylamine by a method similar to Example 101(amidation) to yield the title compound.

Melting point: 251°-252° C. (recrystallized from ethyl acetate-isopropylether)

The compounds of Example 258-263 were obtained from the1,2-dihydro-2-oxo-3-quinolinecarboxylic acids and amines, which havesubstituents corresponding to each Example, by a method sirnilar toExample 257 (amidation).

EXAMPLE 258 N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N-methyl-2-oxo-4-phenyl-3-quinolinecarboxamide

Melting point: 262°-264° C. (recrystallized from ethyl acetate hexane)NMR (200 MHz, CDCl₃) ppm: 2.87 (3H, s), 4.61 (1H, d, J=15 Hz), 4.75 (1H,d, J=15 Hz), 7.10-7.60 (9H, m), 7.66 (2H, s), 7.78 (1H, s), 12.44 (1H,bs)

EXAMPLE 259 N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-1-methyl-2-oxo-4-phenyl-3-quinolinecarboxamide

Melting point: 191°-192° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 260 N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N,1-dimethyl-2-oxo-4-phenyl-3-quinolinecarboxamide

Melting point: 163°-164° C. (recrystallized from ethyl ether-hexane) NMR(200 MHz, CDCl₃) ppm: 2.83 (3H, s), 3.83 (3H, s), 4.29 (1H, d, J=15 Hz),5.00 (1H, d, J=15 Hz), 7.16 (2H, m), 7.24-7.70 (9H, m), 7.75 (1H, s)

EXAMPLE 261 N-3,5-Bis(trifluoromethyl)benzyl!-4-(2-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-3-quinolinecarboxamide

A white form

NMR (200 MHz, CDCl₃) ppm: 3.87 (3H, s), 4.54 (1H, dd, J=16, 5.6 Hz),4.69 (1H, dd, J=16, 6.5 Hz), 7.05-7.53 (7H, m), 7.68 (1H, m), 7.69 (2H,s), 7.73 (1H, s), 9.17 (1H, bs)

EXAMPLE 262 N-3,5-Bis(trifluoromethyl)benzyl!-4-(2-chlorophenyl)-1,2-dihydro-N,1-dimethyl-2-oxo-3-quinolinecarboxamide

Melting point: 189°-190° C. (recrystallized from ethyl acetate-hexane)NMR (200 MHz, CDCl₃) ppm: 2.94 (3H, s), 3.84 (3H, s), 4.25 (1H, d, J=15Hz), 5.08 (1H, d, J=15 Hz), 7.03-7.23 (2H, m), 7.32-7.65 (8H, m), 7.75(1H, s)

EXAMPLE 263 N-3,5-Bis(trifluoromethyl)benzyl!-4-(2-chlorophenyl)-1,2-dihydro-N,1,6-trimethyl-2-oxo-3-quinolinecarboxamide

Melting point: 226°-227° C. (recrystallized from ethylacetate-isorpropyl ether)

EXAMPLE 264 N-3,5-Bis(trifluoromethyl)benzyl!-6-chloro-N-methyl-4-phenyl-3-quinolinecarboxamide

6-Chloro-4-phenylquinoline-3-carboxylic acid was reacted with N-3,5-bis(trifluoromethyl)benzyl!methylamine by a method similar toExample 101 (amidation) to yield the title compound.

Melting point: 105°-106° C. (recrystallized from ethyl acetate-hexane)NMR (200 MHz, CDCl₃) ppm: 2.60 (3×4/5H, s), 2.81 (3/5H, s), 4.0-5.2 (2H,b), 7.29-7.81 (10H, m), 8.16 (1H, d, J=8.8 Hz), 8.91 (1H, s)

EXAMPLE 265 N-3,5-Bis(trifluoromethyl)benzyl!-N-methyl-4-phenyl-3-quinolinecarboxamide

The compound obtained in Example 264 was reacted by a method similar toExample 224 (catalytic reduction) to yield the title compound.

Melting point: 96°-97° C. (recrystallized from ethyl acetate-hexane) NMR(200 MHz, CDCl₃) ppm: 2.61 (3×6/7H, s), 2.81 (3/7H, s), 4.0-5.2 (2H, b),7.28-7.83 (11H, m), 8.22 (1H, d, J=8.8 Hz), 8.93 (1H, s)

The compounds of Example 266-268 were obtained from thequinoline-3-carboxylic acids and amines, which have substituentscorresponding to each Example, by a method similar to Example 264(amidation)

EXAMPLE 266 N-3,5-Bis(trifluorornethyl)benzyl!-2-methyl-4-phenyl-3-quinolinecarboxamide

Melting point: 191°-192° C. (recrystallized from ethyl ether-hexane)

EXAMPLE 267 N-3,5-Bis(trifluoromethyl)benzyl!-N,2-dimethyl-4-phenyl-3-quinolinecarboxamide

Melting point: 146°-147° C. (recrystallized from ethyl ether-hexane) NMR(200 MHz, CDCl₃) ppm: 2.61 (3H, s), 2.74 (3H, s), 4.42 (1H, d, J=15 Hz),4.77 (1H, d, J=15 Hz), 7.20-7.85 (11H, m), 8.09 (1H, d, J=8.8 Hz)

EXAMPLE 268 N-3,5-Bis(trifluororaethyl)benzyl!-2,6,7-trimethoxy-N-raethyl-4-phenyl-3-quinolinecarboxamide

Melting point: 88°-89° C. (recrystallized from isorpopyl ether-hexane)

EXAMPLE 269 N-3,5-Bis(trifluororaethyl)benzyl!-2-chloro-N-methyl-4-phenyl-3-quinolinecarboxamide

A mixture of the compound obtained in Example 258 (2.55 g) andphosphorus oxychloride (60 ml) was stirred for 2 hours with heatingunder reflux. The solvent was evaporated and the residue was dissolvedin ethyl acetate. The solution was washed with cooled aqueous sodiumhydrogen carbonate and water, dried and evaporated to yield the titlecompound as colorless crystals (2.45 g).

Melting point: 147°-148° C. (recrystallized from ether acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.71 (3H, s), 4.54 (1H, d, J=14.9 Hz),4.71 (1H, d, J=14.9 Hz), 7.20-8.13 (h, m), 8.11 (1H, d, J=8.4 Hz)

EXAMPLE 270 N-3,5-Bis(trifluororaethyl)benzyl!-2-methoxy-N-methyl-4-phenyl-3-quinolinecarboxamide

To a solution of the compound obtained in Example 269 (100 mg) inmethanol (2 ml) was added 28% NaOMe-methanol (2 ml), and the mixture wasstirred for 3 hours with heating under reflux. The solvent wasevaporated and the residue was dissolved in ethyl acetate. The solutionwas washed with water, dried and evaporated to yield the title compoundas colorless crystals (85 mg).

Melting point: 146°-147° C. (recrystallized frora ether acetate-hexane)NMR (200 MHz, CDCl₃) ppm: 2.70 (2H, s), 2.72 (1H, s), 3.82 (1/3H, d,J=15.7 Hz), 4.15 (1H, s), 4.18 (2H, s), 4.39 (2/3H, d, J=15 Hz), 4.62(1/3H, d, J=15.7 Hz), 4.89 (2/3H, d, J=15.6 Hz), 17.7-7.95 (12H, m)

EXAMPLE 271 N-3,5-Bis(trifluoromethyl)benzyl!-N-methyl-2-methylamino-4-phenyl-3-quinolinecarboxamide

To a solution of the corapound obtained in Example 269 (100 mg) inethanol (4 ml) was added 40% MeNH₂ -methanol (12 ml), and the mixturewas stirred for 4 hours with heating under reflux. The solvent wasevaporated and the residue was dissolved in ethyl acetate. The solutionwas washed with water, dried and evaporated to yield the title compoundas colorless crystals (65 mg).

Melting point: 173°-174° C. (recrystallized from ethyl acetate-hexane)NMR (200 MHz, CDCl₃) ppm: 2.57 (2H, s), 2.62 (1H, s), 3.13 (2H, d, J=4.8Hz), 3.14 (1H, d, J=5 Hz), 3.52 (1/3H, d, J=15.8 Hz), 4.39 (2/3H, d,J=14.5 Hz), 4.60 (1/3H, d, J=15.8 Hz), 4.69 (2/3H, d, J=14.5 Hz), 5.14(2/3H, b), 5.32 (1/3H, b), 7.12-7.85 (12H, m)

EXAMPLE 272 N-3,5-Bis(trifluoromethyl)benzyl!-N-methyl-2-methylthio-4-phenyl-3-quinolinecarboxamide

To a solution of the compound obtained in Example 269 (100 mg) in THF (6ml)-methanol (2 ml) was added 15% MeSNa in water (4 ml), and the mixturewas stirred for 8 hours with heating under reflux. The solvent wasevaporated and the residue was dissolved in ethyl acetate. The solutionwas washed with water, dried and evaporated to yield the title compoundas colorless crystals (55 mg).

Melting point: 144°-145° C. (recrystallized from ethyl acetate-hexane)NMR (200 MHz, CDCl₃) ppm: 2.65 (3H, s), 2.77 (3H, s), 4.50 (1H, d, J=15HZ), 4.70 (1H, d, J=15 Hz), 7.29-8.05 (12H, m)

EXAMPLE 273 N-3,5-Bis(trifluoromethyl)benzyl!-1-chloro-4-(4-fluorophenyl)-N-methyl-3-isoquinolinecarboxamide

The compound obtained in Example 178 (200 mg) was reacted withphosphorus oxychloride (3 ml) by a method similar to Example 269 toyield the title compound as colorless crystals (165 mg).

Melting point: 142°-143° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.79 (2H, s), 2.86 (1H, s), 4.43 (2/3H,s), 4.69 (4/3H, s), 7.06-7.81 (10H, m), 8.44-8.49 (1H, m)

EXAMPLE 274 N-3,5-Bis(trifluoromethyl)benzyl!-4-(4-fluorophenyl)-N-methyl-3-isoquinolinecarboxamide

The compound obtained in Example 273 was reacted by a method similar toExample 224 (catalytic reduction) to yield the title compound ascolorless crystals.

Melting point: 134°-135° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.76 (3×5/7H, s), 2.85 (3×2/7H, s),4.39 (2×2/7, s), 4.71 (2×5/7H, s), 7.07-7.81 (10H, m), 8.07-8.12 (1H,m), 9.28 (2/7H, s), 9.32 (5/7H, s)

EXAMPLE 275 N-3,5-Bis(trifluoromethyl)benzyl!-1-chloro-N-methyl-4-phenyl-3-isoquinolinecarboxamide

The compound obtained in Example 172 was reacted with phosphorusoxychloride by a method similar to Example 269 to yield the titlecompound as colorless crystals.

Melting point: 176°-177° C. (recrystallized from ethyl acetate-hexane)NMR (200 MHz, CDCl₃) ppm: 2.75 (3×3/4H, s), 2.82 (3/4H, s), 4.42 (1/2H,s), 4.67 (3/2H, s), 7.30-7.83 (11H, m), 8.46 (1H, m)

EXAMPLE 276 N-3,5-Bis(trifluoromethyl)benzyl!-N-methyl-4-phenyl-3-isoquinolinecarboxamide

The compound obtained in Example 275 was reacted by a method similar toExample 224 (catalytic reduction) to yield the title compound ascolorless crystals.

Melting point: 139°-140° C. (recrystallized from hexane) NMR (200 MHz,CDCl₃) ppm: 2.73 (3×3/4H, s), 2.82 (3/4H, s) 4.36 (1/2H, s), 4.70 (3/2H,s), 7.33-7.82 (11H, m), 8.10 (1H, m), 9.32 (1H, m)

EXAMPLE 277 N-3,5-Bis(trifluoromethyl)benzyl!-1-methoxy-N-methyl-4-phenyl-3-isoquinolinecarboxamide

The compound obtained in Example 275 was reacted with sodium methoxideby a method similar to Example 270 to yield the title compound ascolorless crystals.

Melting point: 129°-130° C. (recrystallized from isopropyl ether-hexane)NMR (200 MHz, CDCl₃) ppm: 2.75, 2.77 (total 3H, each s), 4.07 (2/5×3H,s), 4.19 (3/5×3H, s), 4.36 (2/5×2H, s), 4.68(3/5×2H, s), 7.28-7.70 (9H,m), 7.78 (2H, m), 8.31 (1H, m)

EXAMPLE 278 N-3,5-Bis(trifluoromethyl)benzyl!-N-methyl-1-methylamino-4-phenyl-3-isoquinolinecarboxamide

The compound obtained in Example 275 was reacted with methylamine by amethod similar to Example 271 to yield the title compound as colorlesscrystals.

Melting point: 213°-214° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.74, 2.77 (total 3H, each s), 3.11(3/7×3H, d, J=5.0 Hz), 3.22 (4/7×3H, d, J=4.8 Hz), 4.39 (3/7×2H, s),4.68 (4/7×2H, s), 5.44 (1H, m), 7.33-7.67 (10H, m), 7.79 (2H, bs)

EXAMPLE 279 3,4-cis-N-3,5-Bis(trifluoromethyl)benzyl!-1,2,3,4-tetrahydro-N,2-dimethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide

3,4-cis-1,2,3,4-Tetrahydro-2-methyl-1-oxo-4-phenyl-3-isoquinolinecarboxlicacid prepared from 2-methyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylicacid methyl ester, by converting to the reduced compound (3,4-cis) bystirring for 6 hours at 90° C. in the presence of 10% palladium-carbonin acetic acid in a hydrogen atmosphere, followed by hydrolysis inhydrochloric acid-acetic acid at 110° C.! was reacted with N-3,5-bis(trifluoromethyl)benzyl!methylamine by a method similar toExample 101 to yield the title compound.

Melting point: 226°-227° C. (recrystallized from ethyl acetate-ethylether)

EXAMPLE 280 3,4-trans-N-3,5-Bis(trifluoromethyl)benzyl!-4-(4-fluorophenyl)-1,2,3,4-tetrahydro-N,2-dimethyl-1-oxo-3-isoquinolinecarboxamide

The compound obtained in Reference Example 2 was reacted with N-3,5-bis(trifluoromethyl)benzyl!methylamine by a method similar toExample 101 to yield the title compound.

Melting point: 171°-172° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 281 3,4-cis-N-3,5-Bis(trifluoromethyl)benzyl!-3,4-dihydro-N-methyl-1-oxo-4-phenyl-1H-2-benzopyran-3-carboxamide

3,4-cis-3,4-Dihydro-1-oxo-4-phenyl-1H-2-benzopyran-3-carboxylic acidprepared from 1-oxo-4-phenyl-1H-2-benzopyran-3-carboxylic acid bystirring for 4 hours at 90° C. in the presence of 10% palladium-carbonin acetic acid in a hydrogen atmosphere! was reacted with N-3,5-bis(trifluoromethyl)benzyl!methylamine by a method similar toExample 101 to yield the title compound.

Melting point: 160°-161° C. (recrystallized from ethyl acetate-isopropylether)

EXAMPLE 282 N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N-methyl-1-oxo-4-phenyl-2-2-(N,N,N-trimethylammonium)ethyl!-3-isoquinolinecarboxamide

A solution of the compound obtained in Example 184 (free form) (65 mg)in methanol (2 ml) was added methyl iodide (0.5 ml), and the mixture wasstirred at room temperature for 1.5 hours. Evaporation of the solventyielded the title compound as colorless crystals (72 mg).

Melting point: 242°-243° C. (recrystallized frommethanol-dichloromethane-ethyl ether) NMR (200 MHz, CDCl₃) ppm: 3.02(3H, s), 3.65 (9H, s), 3.70-4.05 (2H, b), 4.34 (1H, d, J=14.2 Hz),4.52-4.80 (1H, b), 4.90-5.15 (1H, b), 5.42 (1H, d, J=14.2 Hz), 7.05-7.30(6H, m), 7.42 (2H, s), 7.58 (2H, m), 7.76 (1H, s), 8.44 (1H, m)

EXAMPLE 283 N-3,5-Bis(trifluoromethyl)phenyl!-6-chloro-1,2-dihydro-N-methyl-1-oxo-4-phenyl-3-isoquinolineacetamide

The compound obtained Example 223 was reacted by a method similar toExample 102(C) to yield the title compound.

Melting point: 181°-182° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.51 (2H, b), 3.30 (3H, s), 3.67 (3H,s), 6.92 (1H, bd, J=1.8 Hz), 7.10-7.65 (8H, m), 7.76 (1H, bs), 8.44 (1H,d, J=8.6 Hz)

EXAMPLE 284 3,5-Bis(trifluoromethyl)benzyl1,2-dihydro-2-methyl-1-oxo-4-phenyl-3-isoquinolinecarboxylate

A mixture of 2-methyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylic acid(140 mg), acetone (5 ml), DMF (1 ml), potassium carbonate (70 mg) and3,5-bis(trifluoromethyl)benzyl bromide (0.11 ml) was stirred withheating under reflux for 1 hour, and then concentrated. To theconcentrate was added water, and the mixture was extracted withd ethylacetate. The extract was washed with water, dried, and evaporated toyield the title compound as colorless crystals (185 mg).

Melting point: 153°-154° C. (recrystallized from methanol-ethyl ether)

EXAMPLE 285 N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N,2-dimethyl-4-phenyl-1-thioxo-3-isoquinolinecarboxamide

A mixture of the compound obtained in Example 157 (52 mg), dioxane (3ml) and phosphorous pentasulfide (44 mg) was refluxed for 4 hours. Tothe mixture was added water, and extracted with ethyl acetate. Theextract was washed with aqueous sodium hydrogen carbonate and water,dried and evaporated. The residue was purified by silica gel columnchromatography to yield the title compound as colorless crystals (35mg).

Melting point: 145°-147° C. (recrystallized from ethyl acetate-hexane)NMR (200 MHz, CDCl₃) ppm: 2.79 (3H, s), 4.18 (3H, s), 4.24 (1H, d,J=14.6 Hz), 4.80 (1H, d, J=14.6 Hz), 7.16-7.89 (6H, m), 7.51 (2H, s),7.60 (2H, m), 7.81 (1H, s), 9.23 (1H, m)

The compounds of Example 286 to 289 were obtained using thecorresponding 2-oxo-2H-1-benzopyran-3-acetic acids and anilies by amethod similar to Example 1(A).

EXAMPLE 286 N-2,6-Bis(2,2,2-trifluoroethoxy)phenyl!-6-chloro-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-acetamide

Melting point: 214°-216° C. (recrystallized from isopropyl ether--ethylacetate) NMR (200 MHz, CDCl₃) ppm: 2.07 (3H, s), 3.34 (1H, d, J=14.0Hz), 3.54 (1H, d, J=13.6 Hz), 4.33 (4H, q, J=8.2 Hz), 6.67 (2H, d, J=8.4Hz), 6.85 (1H, d, J=2.2 Hz), 7.17 (1H, d, J=8.4 Hz), 7.23-7.51 (6H, m),7.60 (1H, bs)

EXAMPLE 2876-Chloro-4-(2-methylphenyl)-2-oxo-N-(2,4,6-trifluorophenyl)-2H-1-benzopyran-3-acetamide

Melting point: 225°-227° C. (recrystallized from isopropyl ether--ethylacetate) NMR (200 MHz, CDCl₃) ppm: 2.08 (3H, s), 3.38 (1H, d, J=13.6Hz), 3.54 (1H, d, J=14.2 Hz), 6.70 (2H, ddd, J=1.2, 8.6, 8.6 Hz), 6.87(1H, d, J=2.4 Hz), 7.10-7.19 (1H, m), 7.33-7.53 (5H, m), 7.65 (1H, bs)

EXAMPLE 2886-Chloro-2-oxo-4-(2-trifluoromethylphenyl)-N-(2,4,6-trifluorophenyl)-2H-1-benzopyran-3-acetamide

Melting point: 247°-249° C. (recrystallized from ethyl acetate) NMR (200MHz, CDCl₃) ppm: 3.10 (1H, d, J=14.4 Hz), 3.73 (1H, d, J=14.2 Hz),6.65-6.76 (3H, m), 7.34-7.50 (3H, m), 7.59 (1H, bs), 7.62-7.80 (2H, m),7.90 (1H, dd, J=1.6, 7.0 Hz)

EXAMPLE 289 N-2,6-Bis(2,2,2-trifluoroethoxy)phenyl!-6-chloro-4-(2-methoxyphenyl)-2-oxo-2H-1-benzopyran-3-acetamide

Melting point: 243°-245° C. (recrystallized from ethyl acetate) NMR (200MHz, CDCl₃) ppm: 3.35 (1H, d, J=14.0 Hz), 3.63 (1H, d, J=14.2 Hz), 3.70(3H, s), 4.22-4.38 (4H, m), 6.69 (2H, d, J=8.4 Hz), 6.94 (1H, d, J=2.2Hz), 7.08 (1H, d, J=8.6 Hz), 7.13-7.35 (4H, m), 7.42-7.58 (2H, m), 7.63(1H, bs)

Reference Example 14-(2-Chlorophenyl)-6,7-dimethyl-2-(1-methylethyloxy)-3-quinolinecarboxylicacid

Process 1:

To a solution of4-(2-chlorophenyl)-1,2-dihydro-6,7-dimethyl-2-oxo-3-quinolinecarboxylicacid ethyl ester (2.0 g) in DMF (20 ml) was added sodium hydride (60% inoil) (270 mg), followed by stirring at room temperature for 30 minutes.To this solution was added isopropyl iodide (0.9 ml), followed bystirring at 70° C. for 5 hours. After the mixture was cooled, ethylacetate was added, and this mixture was washed successively wfth dilutehydrochloric acid, aqueous potassium carbonate and Water and then dried,after which the solvent was distilled off. The residue was subjected tosilica gel column chromatography (hexane:ethyl acetate=5:1), to yield4-(2-chlorophenyl)-6,7-dimethyl-2-(1-methylethyloxy)-3-quinolinecarboxylicacid ethyl ester as colorless crystals (1.72 g).

Melting point: 96°-97° C. (recrystallized from ethyl ether-hexane) NMR(200 MHz, CDCl₃) ppm: 1.01 (3H, t, J=7.1 Hz), 1.42 (6H, d, J=6.2 Hz),2.26 (3H, s), 2.41 (3H, s), 4.00-4.16 (2H, m), 5.57 (1H, m), 6.92 (1H,s), 7.20-7.55 (4H, m), 7.64 (1H, s)

Elemental analysis (for C₂₃ H₂₄ NO₃ Cl):

Calculated (%): C, 69.43; H, 6.08; N, 3.52

Found (%): C, 69.19; H, 5.99; N, 3.40

Process 2:

To the compound obtained in Process 1 (1.64 g) were added ethanol (28ml), water (7 ml) and potassium hydroxide (1.09 g), followed by heatingunder reflux for 1 hour. After the solvent was distilled off, theresidue was acidified with dilute hydrochloric acid and then-extractedwith ethyl acetate. The extract was washed with saturated aqueous sodiumchloride and dried, after which the solvent was distilled off, to yieldthe title compound as colorless crystals (1.31 g).

Melting point: 184°-186° C. (recrystallized from ethyl acetate-hexane)NMR (200 MHz, CDCl₃) ppm: 1.49 (6H, d, J=6.2 Hz), 2.26 (3H, s), 2.43(3H, s), 5.73 (1H, m), 6.92 (1H, s), 7.10-7.60 (4H, m), 7.66 (1H, s)

Elemental analysis (for C₂₁ H₂₀ NO₃ Cl):

Calculated (%): C, 68.20; H, 5.45; N, 3.79

Found (%): C, 68.23; H, 5.47; N, 3.78

Reference Example 23,4-trans-4-(4-Fluorophenyl)-1,2,3,4-tetrahydro-2-methyl-1-oxo-3-isoquinolinecarboxylicacid

Process 1:

A mixture of 2-(4-fluorobenzoyl)benzoic acid (3.00 g),1-hydroxybenzotriazole (2.07 g), 1,3-dicyclohexylcarbodiimide (3.00 g)and anhydrous THF (50 ml) was stirred at room temperature for 1 hour. Tothis mixture were added N-methylglycine ethyl ester hydrochloride (2.84g) and triethylamine (2.58 ml), followed by stirring at room temperaturefor 16 hours and with heating and refluxing for 4 hours. After thesolvent was distilled off, ethyl acetate was added to the residue, andthe insoluble crystals were separated by filtration. The flitrate waswashed successively with water, aqueous sodium hydrogen carbonate,water, dilute hydrochloric acid and water and then dried, after whichthe solvent was distilled off, to yield N-2-(4-fluorobenzoyl)benzoyl!-N-methylglycine ethyl ester as a colorlessoily substance (4.2 g).

NMR (200 MHz, CDCl₃) ppm: 1.27, 1.30 (total 3H, each t, J=7.0 Hz), 3.01,3.06 (total 3H, each s), 4.01, 4.17 (total 2H, each s), 4.15-4.20 (2H,m), 7.0-7.9 (8H, m)!

To a solution of this oily substance in toluene (100 ml) was added1,8-diazabicyclo 5.4.0!undec-7-en(3.0 ml), followed by heating underreflux for 2 hours. After the solvent was distilled off, ethyl acetatewas added to the residue. This mixture was washed successively withwater, 10% aqueous potassium hydrogen sulfate and water and then dried,after which the solvent was distilled off, to yield4-(4-fluorophenyl)-3,4-dihydro-4-hydroxy-2-methyl-1(2H)-isoquinoline-3-carboxylicacid ethyl ester as colorless crystals. To a suspension of the crystalsin toluene (100 ml) was added p-toluenesulfonic acid hydrate (3.0 g),followed by heating under reflux for 14 hours with a water separator.The solvent was distilled off, and ethyl acetate was added to theresidue. This mixture was washed successively with water, aqueous sodiumhydrogen carbonate and water and then dried, after which the solvent wasdistilled off, to yield4-(4-fluorophenyl)-2-methyl-1(2H)-isoquinoline-3-carboxylic acid ethylester as colorless crystals (3.12 g).

Melting point: 172°-173° C. (recrystallized from ethyl acetate-hexane)NMR (200 MHz, CDCl₃) ppm: 1.00 (3H, t, J=7.0 Hz), 3.62 (3H, s), 4.07(2H, q, J=7.0 Hz), 7.11-7.35 (5H, m), 7.53-7.60 (2H, m), 8.50-8.55 (1H,m)

Elemental analysis (for C₁₉ H₁₆ NO₃ F):

Calculated (%): C, 70.15; H, 4.96; N, 4.31

Found (%): C, 70.01; H, 4.86; N, 4.20

Process 2:

A mixture of the compound obtained in Process 1 (2.70 g), acetic acid(50 ml) and 5% palladium-carbon (2.00 g) was stirred at 70° C. in ahydrogen atmosphere for 1 hour. After the mixture was cooled and thenfiltered, the filtrate was distilled to remove the solvent. The residuewas dissolved in ethyl acetate and washed successively with water,aqueous potassium carbonate and water and then dried, after which thesolvent was distilled off, to yield3,4-cis-4-(4-fluorophenyl)-1,2,3,4-tetrahydro-2-methyl-1-oxo-3-isoquinolinecarboxylicacid ethyl ester as colorless crystals (2.43 g).

Melting point: 151°-153° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 0.98 (3H, t, J=7.2 Hz), 3.12 (3H, s),3.78-4.03 (2H, m), 4.25 (1H, d, J=7.0 Hz), 4.92 (1H, d, J=7.0 Hz),6.90-7.41 (7H, m), 8.20-8.26 (1H, m)

Elemental analysis (for C₁₉ H₁₈ NO₃ F):

Calculated (%): C, 69.71; H, 5.54; N, 4.28

Found (%): C, 69.44; H, 5.19; N, 4.31

Process 3:

To a suspension of the compound obtained in Process 2 (2.43 g) inethanol (50 ml) and THF (15 ml) was added 2N-NaOH (14 ml) at 0° C. Afterthis mixture was stirred at room temperature for 1 hour, the solvent wasdistilled off. Water was added to the residue, which was then washedwith ethyl ether, after which the water layer was acidified with 2N-HCl.This mixture was extracted with ethyl acetate, the extract being washedwith water and dried, followed by solvent removal by distillation, toyield the title compound as colorless crystals (2.12 g).

Melting point: 248°-250° C. (recrystallized from ethyl acetate-ethylether) NMR (200 MHz, CDCl₃ +DMSO-d₆) ppm: 3.04 (3H, s), 4.16 (1H, s),4.73 (1H, s), 6.90-7.17 (5H, m), 7.41-7.44 (2H, m), 8.16-8.21 (1H, m)

Elemental analysis (for C₁₇ H₁₄ NO₃ F):

Calculated (%): C, 68.22; H, 4.71; N, 4.68

Found (%): C, 68.02; H, 4.72; N, 4.58

Reference Example 33,4-trans-4-(2-Chlorophenyl)-1,2,3,4-tetrahydro-1,6,7-trimethyl-2-oxo-3-quinolinecarboxylicacid

Process 1:

To a suspension of lithium aluminum hydride (1.4 g) in THF (50 ml) wasadded dropwise a solution of4-(2-chlorophenyl)-1,2,-dihydro-1,6,7-trimethyl-2-oxo-3-quinolinecarboxylicacid ethyl ester (10.0 g) in THF (100 ml) at 0° C. After this mixturewas stirred at 0° C. for 30 minutes, water (4 ml) was added, followed bystirring at room temperature for 30 minutes. The insoluble material wasfiltered off, the filtrate being concentrated. After ethyl acetate wasadded, the residue was washed successively with dilute hydrochloric acidand water and then dried, followed by soIvent removal by distillation.The residue was subjected to silica gel column chromatography(hexane:ethyl acetate=3:1) to yield3,4-trans-4-(2-chlorophenyl)-1,2,3,4-tetrahydro-1,6,7-trimethyl-2-oxo-3-quinolinecarboxylicacid ethyl ester as colorless crystals (2.94 g).

Melting point: 147°-148° C. (recrystallized from ethyl acetate-isopropylester) NMR (200 MHz, CDCl₃) ppm: 1.10 (3H, t, J=7.0 Hz), 2.14 (3H, s),2.29 (3H, s), 3.43 (3H, s), 3.97 (1H, d, J=7.2 Hz), 4.09 (2H, q, J=7.0Hz), 5.07 (1H, d, J=7.2 Hz), 6.64 (1H, s), 6.80-6.90 (1H, m), 6.89 (1H,s), 7.10-7.30 (2H, m), 7.40-7.50 (1H, m)

Elemental analysis (for C₂₁ H₂₂ NO₃ Cl):

Calculated (%): C, 67.83; H, 5.96; N, 3.77

Found (%): C, 67.98; H, 6.05; N, 3.98

Process 2:

A mixture of the compound obtained in Process 1 (1.50 g), THF (10 ml),ethanol (20 ml), water (2 ml) and sodium hydroxide (0.75 g) was stirredat room temperature for 3 hours, after which the soivent was distilledoff to an about half mount. After water was added, the residue waswashed with ether. The water layer was acidified with dilutehydrochloric acid and extracted with ethyl acetate. The extract waswashed with saturated aqueous sodium chloride and then dried, afterwhich the solvent was distilled off, to yield the title compound ascolorless crystals (1.26 g).

Melting point: 128°-129° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.15 (3H, s), 2.29 (3H, s), 3.42 (3H,s), 3.93 (1H, d, J=5.2 Hz), 5.07 (1H, d, J=5.2 Hz), 6.70-6.80 (1H, m),6.74 (1H, s), 6.89 (1H, s), 7.03-7.45 (3H, m)

Elemental analysis (for C₁₉ H₁₈ NO₃ Cl):

Calculated (%): C, 66.38; H, 5.28; N, 4.07

Found (%): C, 66.22; H, 5.16; N, 4.03

Reference Example 43,4-trans-6-Chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinolinecarboxylicacid

Process 1:

6-Chloro-1,2-dihydro-1-methyl-2-oxo-4-phenyl-3-quinolinecarboxylic acidethyl ester was reacted in substantially the same manner as in Process 1of Reference Example 3 to yield3,4trans-6-chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinolinecarboxylicacid ethyl ester as colorless crystals.

Melting point: 83°-84° C. (recrystallized from ethyl ether-hexane) NMR(200 MHz, CDCl₃) ppm: 1.05 (3H, t, J=7.1 Hz), 3.41 (3H, s), 3.89 (1H, d,J=9.4 Hz), 4.00-4.15 (2H, m), 4.58 (1H, d, J=9.4 Hz), 6.85 (1H, d, J=1.8Hz), 7.00 (1H, d, J=8.6 Hz), 7.10-7.40 (6H, m)

Elemental analysis (for C₁₉ H₁₈ NO₃ Cl):

Calculated (%): C, 66.38; H, 5.28; N, 4.07

Found (%): C, 66.36; H, 5.16; N, 4.12

Process 2:

The compound obtained in Process 1 was reacted in substantially the samemanner as in Process 2 of Reference Example 3 to yield the titlecompound as colorless crystals.

Melting point: 138°-139° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 3.41 (3H, s), 3.93 (1H, d, J=8.0 Hz),4.58 (1H, d, J=8.0 Hz), 5.20 (1H, bs), 6.80-7.40 (8H, m)

Elemental analysis (for C₁₇ H₁₄ NO₃ Cl):

Calculated (%): C, 64.67; H, 4.47; N, 4.44

Found (%): C, 64.35; H, 4.52; N, 4.57

Reference Example 53,4-trans-4-(2-Chlorophenyl)-1,2,3,4-tetrahydro-1,6,7-trimethyl-3-quinolinecarboxylicacid

Process 1:

To a mixture of 4-(2-chlorophenyl)-6,7-dimethyl-3-quinolinecarboxylicacid ethyl ester (26.5 g), sodium borohydride (6.0 g) and ethanol (150ml) was heated under reflux for 2 hours. After the solvent was distilledoff, water was added to the residue, followed by extraction with ethylacetate. After the extract was washed with water and dried, the solventwas distilled off. The residue was subjected to silica gel columnchromatography (ethyl acetate:hexane=3:1) to yield4-(2-chlorophenyl)-1,4-dihydro-6,7-dimethyl-3-quinolinecarboxylic acidethyl ester as colorless crystals (5.0 g).

Melting point: 204°-209° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.13 (3H, t, J=7.2 Hz), 2.07 (3H, s),2.12 (3H, s), 3.95-4.15 (2H, m), 5.74 (1H, s), 6.34 (1H, d, J=5.4 Hz),6.46 (1H, s), 6.94 (1H, s), 6.95-7.20 (2H, m), 7.25-7.35 (2H, m), 7.61(1H, d, J=6.2 Hz)

Elemental analysis (for C₂₀ H₂₀ NO₂ Cl):

Calculated (%): C, 70.27; H, 5.90; N, 4.10

Found (%): C, 70.02; H, 5.84; N, 4.07

Process 2:

To a solution of the compound obtained in Process 1 (2.65 g) in DMF (40ml) was added 60% sodium hydride (60% in oil) (0.35 g), followed bystirring at room temperature for 15 minutes. After this mixture wascooled to 0° C., 3 ml of methyl iodide was added, followed by stirringat 0° C. for 30 minutes. After dilute hydrochloric acid was added, themixture was extracted with ethyl acetate. The extract was washed withwater and then dried, after which the solvent was distilled off, toyield4-(2-chlorophenyl)-1,4-dihydro-1,6,7-trimethyl-3-quinolinecarboxylicacid ethyl ester as colorless crystals (2.32 g).

Melting point: 200-201° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.12 (3H, t, J=7.2 Hz), 2.09 (3H, s),2.19 (3H, s), 3.35 (3H, s), 3.95-4.10 (2H, m), 5.74 (1H, s), 6.62 (1H,s), 6.97 (1H, s), 6.98-7.15 (2H, m), 7.20-7.35 (2H, m), 7.52 (1H, s)

Elemental analysis (for C₂₁ H₂₂ NO₂ Cl·0.1H₂ O):

Calculated (%): C, 70.52; H, 6.26; N, 3.92

Found (%): C, 70.39; H, 6.32; N, 3.82

Process 3:

While stirring at room temperature a mixture of the compound obtained inProcess 2 (2.2 g), methanol (30 ml), methanol containing 20% hydrogenchloride (10 ml) and THF (10 ml), a solution of sodium cyanoborohydride(1.0 g) in methanol (15 ml) was gradually added dropwise. After stirringat room temperature for 1 hour, the mixture was alkalinized with aqueouspotassium carbonate and then extracted with ethyl acetate. The extractwas washed with saturated aqueous sodium chloride and dried, after whichthe solvent was distilled off, to yield4-(2-chlorophenyl)-1,2,3,4-tetrahydro-1,6,7-trimethyl-3-quinolinecarboxylicacid ethyl ester as a pale yellow oily substance (2.44 g).

NMR (200 MHz, CDCl₃) ppm: 1.13 (3H, t, J=7.1 Hz), 2.04 (3H, s), 2.21(3H, s), 2.93 (2.5H, s), 3.00-3.50 (3H, m), 3.01 (0.5H, s), 4.00-4.18(2H, m), 4.95 (0.87H, d, J=5.8 Hz), 5.09 (0.13H, d, J=5.4 Hz), 6.45-6.66(2H, m), 6.85-7.45 (4H, m)

Process 4:

To the compound obtained in Process 3 (2.37 g) were added ethanol (40ml), water (10 ml) and potassium hydroxide (2.0 g), followed by stirringat room temperature overnight. After the solvent was distilled off, theresidue was weakly acidified (pH 3 to 4) with dilute hydrochloric acidand then extracted with ethyl acetate. The extract was washed withsaturated aqueous sodium chloride and dried, after which the solvent wasdistilled off, to yield the title compound as colorless crystals (1.51g).

Melting point: 196°-199° C. (recrystallized from ethyl acetate-ethylether) NMR (200 MHz, CDCl₃) ppm: 2.08 (3H, s), 2.23 (3H, s), 3.09 (3H,s), 3.25-3.60 (3H, m), 4.92 (1H, d, J=5.6 Hz), 5.50-6.80 (1H, brs), 6.59(1H, s), 6.90 (1H, s), 6.95 (1H, m), 7.10-7.45 (3H, m)

Elemental analysis (for C₁₉ H₂₀ NO₂ Cl·1.0.7H₂ O):

Calculated (%): C, 66.64; H, 6.30; N, 4.09

Found (%): C, 66.53; H, 6.00; N, 3.85

Reference Example 61,2,3,4-Tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinolineacetic acid

Process 1:

A mixture of 1,2-dihydro-1-methyl-2-oxo-4-phenyl-3-quinolinecarboxylicacid ethyl ester (30.7 g), 10% palladium-carbon (2.0 g) and acetic acid(150 ml) was stirred at 80° C. for 24 hours in a hydrogen atmosphere (5atm). After the catalyst was filtered off, the filtrate wasconcentrated. After ethyl acetate was added, the residue was washedsuccessively with potassium carbonate and water and then dried, afterwhich the solvent was distilled off, to yield3,4-trans-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinolinecarboxylicacid ethyl ester as colorless crystals (27.9 g).

Melting point: 80°-81° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.04 (3H, t, J=7.1 Hz), 3.43 (3H, s),3.91 (1H, d, J=9.6 Hz), 4.00-4.15 (2H, m), 4.16 (1H, d, J=9.6 Hz),6.80-7.40 (9H, m)

Elemental analysis (for C₁₉ H₁₉ NO₃):

Calculated (%): C, 73.77; H, 6.19; N, 4.53

Found (%): C, 73.53; H, 6.12; N, 4.52

Process 2:

A mixture of the compound obtained in Process 1 (20 g), sodium hydride(60% in oil) (2.72 g) and DMF (200 ml) was stirred at room temperaturefor 30 minutes. After methyl bromoacetate (6.73 ml) was added, themixture was stirred at room temperature overnight. After dilutehydrochloric acid was added, the mixture was extracted with ethylacetate. The extract was washed with aqueous potassium carbonate andwater and then dried, followed by solvent removal by distillation. Theresidue was subjected to silica gel column chromatography (hexane:ethylacetate=3:1) to yield3-ethoxycarbonyl-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinolinecarboxylicacid methyl ester as a pale yellow oily substance. To this oilysubstance were added ethanol (160 ml), water (40 ml) and potassiumhydroxide (10 g), followed by overnight heating and refluxing. After thesolvent was distilled off, dilute hydrochloric acid was added, and themixture was extracted with ethyl acetate. The extract was washed withsaturated aqueous sodium chloride and then dried, after which thesolvent was distilled off. After pyridine (100 ml) was added, theresidue was heated under reflux for 30 minutes. After the solvent wasdistilled off, the residue was acidified with dilute hydrochloric acidand then extracted with ethyl acetate. The extract was washed withsaturated aqueous sodium chloride and then dried, after which thesolvent was distilled off, to yield the title compound (trans:cis=about3:2 mixture) as a white foamy substance (19.1 g).

NMR (200 MHz, CDCl₃) ppm: 2.27-2.65 (1.6H, ml, 2.75-3.00 (0.4H, m),3.25-3.60 (1H, m), 3.44 (1.8H, s), 3.48 (1.2H, s), 4.16 (0.6H, d, J=13.0Hz), 4.19 (0.4H, d, J=6.8 Hz), 6.60-6.70 (0.6H, m), 6.90-7.45 (8.4H, m)

Reference Example 74-(2-Chlorophenyl)-1,2,3,4-tetrahydro-1-methyl-2-oxo-3-quinolineaceticacid

Process 1:

4-(2-Chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-3-quinolineacetic acidethyl ester was reacted in substantially the same manner as in Process 1of Reference Example 3 to yield3,4-trans-4-(2-chlorophenyl)-1,2,3,4-tetrahydro-1-methyl-2-oxo-3-quinolinecarboxylicacid ethyl ester as colorless crystals.

Melting point: 131°-133° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.08 (3H, t, J=7.2 Hz), 3.45 (3H, s),4.00-4.20 (2H, m), 4.03 (1H, d, J=8.0 Hz), 5.14 (1H, d, J=8.0 Hz),6.80-7.50 (8H, m)

Elemental analysis (for C₁₉ H₁₈ NO₃ Cl):

Calculated (%): C, 66.38; H, 5.28; N, 4.07

Found (%): C, 66.03; H, 5.17; N, 4.06

Process 2:

The compound obtained in Process 1 was reacted in substantially the samemanner as in Process 2 of Reference Example 6 to yield the titlecompound (trans:cis=about 6:1 mixture) as colorless crystals.

Melting point: 177°-180° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.34 (0.86, dd, J=16.0, 3.8 Hz),2.45-2.80 (0.28, m), 2.67 (0.86H, dd, J=16.0, 8.8 Hz), 3.35-3.70 (1H,m), 3.45 (2.58H, s), 3.49 (0.42H, s), 4.77 (0.86H, d, J=13 Hz), 5.00(0.14H, d, J=7.0 Hz), 6.58 (0.86H, d, 5=7.4 Hz), 6.90-7.55 (7.14H, m)

Elemental analysis (for C₁₈ H₁₆ NO₃ Cl·0.2H₂ O):

Calculated (%): C, 64.85; H, 4.96; N, 4.20

Found (%): C, 64.80; H, 4.74; N, 4.23

Reference Example 81,2,3,4-Tetrahydro-6,7-dimethoxy-1-methyl-2-oxo-4-phenyl-3-quinolineaceticacid

Process 1:

1,2-Dihydro-6,7-dimethoxy-1-methyl-2-oxo-4-phenyl-3-quinolinecarboxylicacid ethyl ester was reacted in substantially the same manner as inProcess 1 of Reference Example 7 to yield3,4-trans-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methyl-2-oxo-4-phenyl-3-quinolinecarboxylicacid ethyl ester as colorless crystals.

Melting point: 157°-159° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.07 (3H, t, J=7.1 Hz), 3.43 (3H, s),3.71 (3H, s), 3.86 (1H, d, J=8.0 Hz), 3.93 (3H, s), 4.00-4.20 (2H, m),4.55 (lH, d, J=8.0 Hz), 6.44 (1H, s), 6.65 (1H, s), 7.10-7.40 (5H, m)

Elemental analysis (for C₂₁ H₂₃ NO₅):

Calculated (%): C, 68.28; H, 6.28; N, 3.79

Found (%): C, 68.11; H, 6.36; N, 3.77

Process 2:

The compound obtained in Process 1 was reacted in substantially the samemanner as in Process 2 of Reference Example 7 to yield the titlecompound a white foamy substance.

NMR (200 MHz, CDCl₃) ppm: 2.32 (0.33H, dd, J=17.0, 6.2 Hz), 2.39 (0.67H,dd, J=16.0, 5.0 Hz), 2.57 (0.67H, dd, J=16.0, 7.4 Hz), 2.83 (0.33H, dd,J=17.0, 7.6 Hz), 3.20-3.60 (1H, m), 3.42 (2H, s), 3.48 (1H, s), 3.62(2H, s), 3.81 (1H, s), 3.92 (3H, s), 4.09 (0.67H, d, J=11.0 Hz), 4.09(0.33H, d, J=6.2 Hz), 6.22 (0.67H, s), 6.60-6.67 (1.33H, m), 6.90-7.40(5H, m)

Reference Example 96-Chloro-1,2,3,4-tetrahydro-1,4-dimethyl-2-oxo-4-phenyl-3-quinolineaceticacid

Process 1:

To a solution of6-chloro-1,2,3,4-tetrahydro-4-methyl-2-oxo-4-phenylquinoline (6.0 g) inDMF (50 ml) was added sodium hydride (60% in oil) (0.98 g), followed bystirring at room temperature for 30 minutes. After this mixture wascooled to 0° C., methyl iodide (3 ml) was added, followed by stirring atroom temperature for further 30 minutes. After dilute hydrochloric acidwas added, the mixture was extracted with ethyl acetate. The extract waswashed with water and then dried, after which the solvent was distilledoff, to yield6-chloro-1,2,3,4-tetrahydro-1,4-dimethyl-2-oxo-4-phenylquinoline ascolorless crystals (5.58 g).

Melting point: 125°-126° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.66 (3H, s), 2.70 (1H, d, J=16.0 Hz),3.20 (1H, d, J=16.0 Hz), 3.24 (3H, s), 6.95 (1H, d, J=8.4 Hz), 7.10-7.35(7H, m)

Elemental analysis (for C₁₇ H₁₆ NOCl):

Calculated (%): C, 71.45; H, 5.64; N, 4.90

Found (%): C, 71.46; H, 5.66; N, 4.88

Process 2:

While stirring at -78° C. in an argon atmosphere a solution of thecompound obtained in Process 1 (5.0 g) in THF (60 ml), a solution of 2Mlithium sodium isopropylamide in THF-heptane (14.6 ml) was addeddropwise. After the mixture was stirred for 30 minutes, a solution ofmethyl bromoacetate (2.9 ml) in THF (15 ml) was added dropwise, followedby stirring at -78° C. for 30 more minutes. After saturated aqueousammonium chloride was added, the mixture was extracted with ethylacetate. The extract was washed successively with dilute hydrochloricacid and water and then dried, followed by solvent removal bydistillation. The residue was subjected to silica gel columnchromatography (hexane:ethyl acetate=2:1) to yield6-chloro-1,2,3,4-tetrahydro-1,4-dimethyl-2-oxo-4-phenyl-3-quinolineaceticacid methyl ester as a colorless oily substance. To this oily substancewere added methanol (64 ml), water (26 ml) and sodium hydroxide (8 g),followed by stirring overnight at room temperature. After the solventwas distilled off, water was added, and the mixture was washed withether. The aqueous layer was acidified with dilute hydrochloric acid andthen extracted with ethyl acetate. The extract was washed with saturatedaqueous sodium chloride and then dried, after which the solvent wasdistilled oil, to yield the title compound as colorless crystals (5.27g) .

Melting point: 166°-168° C. (recrystallized from ethyl acetate-hexane)NMR (200 MHz, CDCl₃) ppm: 1.42 (3H, s), 1.88 (1H, dd, J=16.0, 2.6 Hz),2.69 (1H, dd, J=16.0, 10.0 Hz), 3.42 (3H, s), 3.68 (1H, dd, J=10.0, 2.6Hz), 6.52 (1H, d, J=2.4 Hz), 6.96 (1H, d, J=8.6 Hz), 7.15-7.50 (6H, m)

Elemental analysis (for C₁₉ H₁₈ NO₃ Cl):

Calculated (%): C, 66.38; H, 5.28; N, 4.07

Found (%): C, 66.40; H, 5.12; N, 4.30

Reference Example 104-(2-Chlorophenyl)-1,2,3,4-tetrahydro-1,6,7-trimethyl-2-oxo-3-quinolineaceticacid

The compound obtained in Process 1 of Reference Example 3 was reacted insubstantially the same manner as in Process 2 of Reference Example 6 toyield the title compound (trans:cis=about 5:1 mixture) as colorlesscrystals.

Melting point: 210°-215° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.09 (2.5H, s), 2.16 (0.5H, s), 2.27(3H, s), 2.33 (0.83H, dd, J=16.0, 4.2 Hz), 2.35-2.80 (0.34H, m), 2.66(0.83H, dd, J=16.0, 8.0 Hz), 3.30-3.70 (1H, m), 3.43 (2.5H, s), 3.47(0.5H, s), 4.68 (0.83H, d, J=12.0 Hz), 4.91 (0.17H, d, J=7.0 Hz), 6.33(0.83H, s), 6.80-7.50 (5.17H, m)

Elemental analysis (for C₂₀ H₂₀ NO₃ Cl):

Calculated (%): C, 67.13; H, 5.63; N, 3.91

Found (%): C, 66.88; H, 5.71; N, 3.81

Reference Example 116-Chloro-4-(2-chlorophenyl)-1,2,3,4-tetrahydro-1-methyl-2-oxo-3-quinolineaceticacid

Process 1:

6-Chloro-4-(2-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-3-quinolinecarboxylicacid ethyl ester was reacted in substantially the same manner as inProcess 1 of Reference Example 3 to yield3,4-trans-6-chloro-4-(2-chlorophenyl)-1,2,3,4-tetrahydro-1-methyl-2-oxo-3-quinolinecarboxylicacid ethyl ester as colorless crystals.

Melting point: 103°-104° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.10 (3H, t, J=7.1 Hz), 3.43 (3H, s),4.00-4.20 (2H, m), 4.01 (1H, d, 5=8.2 Hz), 5.11 (1H, d, J=8.2 Hz),6.80-7.50 (7H, m)

Elemental analysis (for C₁₉ H₁₇ NO₃ Cl₂):

Calculated (%): C, 60.33; H, 4.53; N, 3.70

Found (%): C, 60.28; H, 4.35; N, 3.78

Process 2:

The compound obtained in Process 1 was reacted in substantially the samemanner as in Process 2 of Reference Example 6 to yield the titlecompound (trans:cis=about 4:1 mixture) as a white foamy substance.

NMR (200 MHz, CDCl₃) ppm: 2.34 (0.8H, dd, J=16.0, 4.2 Hz), 2.36-2.80(0.4H, m), 2.63 (0.8H, dd, J=16.0, 8.0 Hz), 3.35-3.70 (1H, m), 3.42(2.4H, s), 3.46 (0.6H, s), 4.78 (0.8H, d, J=13 Hz), 4.98 (0.2H, d, J=6.8Hz), 6.54 (0.8H, s), 6.75-7.60 (6.2H, m)

Reference Example 12

6-Chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinolineaceticacid

The compound obtained in Process 1 of Reference Example 4 was reacted insubstantially the same manner as in Process 2 of Reference Example 6 toyield the title compound (trans:cis=about 4:1 mixture) as a white foamysubstance.

NMR (200 MHz, CDCl₃) ppm: 2.25-2.60 (1.8H, m), 2.80-2.95 (0.2H, m),3.20-3.60 (1H, m), 3.41 (2.4H, s), 3.45 (0.6H, s), 4.14 (0.2H, d, J=7.0Hz), 4.16 (0.8H, d, J=12 Hz), 6.63 (0.8H, s), 6.90-7.50 (7.2H, m)

Elemental analysis (for C₁₈ H₁₆ NO₃ Cl):

Calculated (%): C, 65.56; H, 4.89; N, 4.25

Found (%): C, 65.75; H, 4.98; N, 4.18

Reference Example 133,4-cis-6-Chloro-3,4-dihydro-2-oxo-4-phenyl-2H-1-benzopyran-3-aceticacid

Process 1:

To a solution of 6-chloro-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylicacid ethyl ester (4.4 g) in ethanol (300 ml) was added platinum oxide(0.30 g), followed by stirring at room temperature in a hyarogenatmosphere (3 to 4 atm) for 3 hours. After the catalyst was filteredoff, the flitrate was distilled to remove the solvent, followed bytreatment of the residue with isopropyl ether, to yield6-chloro-3,4-dihydro-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylic acidethyl ester as colorless crystals (2.24 g).

Melting point: 93°-95° C. (recrystallized from isopropyl ether) NMR (200MHz, CDCl₃) ppm: 1.09 (3H, t, J=7.0 Hz), 3.95 (1H, d, J=8.2 Hz), 4.11(2H, q, J=7.0 Hz), 6.94 (1H, d, J=2.4 Hz), 7.0-7.3 (7H, m)

Elemental analysis (for C₁₈ H₁₅ O₄ Cl):

Calculated (%): C, 65.36; H, 4.57

Found (%): C, 65.75; H, 4.61

Process 2:

To a solution of the compound obtained in Process 1 (2.20 g) in DMF (20ml) was added sodium hydride (60% in oil) (0.35 g) at room temperature,followed by stirring for 0.5 hours. After methyl bromoacetate (1.4 ml)was added, this mixture was stirred at room temperature for 2 hours,after which dilute hydrochloric acid was added, followed by extractionwith ethyl acetate. The extract was washed with water and dried, afterwhich the solvent was distilled off, followed by treatment of theresidue with isopropyl ether, to yield6-chloro-3-ethoxycarbonyl-3,4-dihydro-3-methoxycarbonylmethyl-2-oxo-4-phenyl-2H-1-benzopyranas colorless crystals.

Melting point: 134°-136° C. (recrystallized from isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 0.99 (3H, t, J=7.0 Hz), 2.69 (1H, d, J=17.8 Hz),3.27 (1H, d, J=17.8 Hz), 4.00 (2H, m), 5.12 (1H, s), 6.82 (1H, bs),7.0-7.1 (3H, m), 7.2-7.3 (1H, m), 7.4-7.5 (3H, m)

Elemental analysis (for C₂₁ H₁₉ O₆ Cl):

Calculated (%): C, 62.61; H, 4.75

Found (%): C, 62.31; H, 4.70

Process 3:

A mixture of the compound obtained in Process 2 (1.5 g), acetic acid (10ml) and hydrochloric acid (5 ml) was heated for 3 hours under reflux,followed by solvent removal by distillation, to yield a mixture of thetitle compound and its stereo isomer as an oily substance. This oilysubstance was treated with ethyl acetate-isopropyl ether to yield thetitle compound as colorless crystals (0.7 g).

Melting point: 117°-119° C. (recrystallized from isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 2.37 (1H, dd, J=18.0 Hz, J=7.2 Hz), 2.86 (1H, dd,J.=17.6 Hz, J=6.4 Hz), 3.62 (1H, m), 4.31 (1H, d, J=6.6 Hz), 7.0-7.4(8H, m)

Elemental analysis (for C₁₇ H₁₃ O₄ Cl):

Calculated (%): C, 64.47; H, 4.14

Found (%): C, 64.35; H, 3.95

Reference Example 143,4-Dihydro-6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-acetic acid

Process 1:

To a solution of 6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylicacid ethyl ester (15.0 g) in acetic acid (150 ml) was added 10%palladium-carbon (3.0 g), followed by stirring at 80° C. in a hydrogenatmosphere (4 to 5 atm) for 4.5 hours. After the catalyst was filteredoff, the filtrate was distilled to remove the solvent, followed bytreatment of the residue with isopropyl ether, to yield3,4-dihydro-6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylic acidethyl ester as colorless crystals (12.5 g).

Melting point: 206°-208° C. (recrystallized from isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 1.07 (3H, t, J=7.0 Hz), 2.25 (3H, s), 3.94 (1H, d,J=7.6 Hz), 4.10 (2H, qd, J=7.0 Hz, J=2.0 Hz), 4.68 (1H, d, J=7.6 Hz),6.75 (1H, bs), 7.0-7.4 (7H, m)

Elemental analysis (for C₁₉ H₁₈ O₄ ·1/4H₂ O):

Calculated (%): C, 72.48; H, 5.92

Found (%): C, 72.24; H, 5.97

Process 2:

The compound obtained in Process 1 was reacted in substantially the samemanner as in Process 2 of Reference Example 13 to yield3-ethoxycarbonyl-3,4-dihydro-3-methoxycarbonylmethyl-6-methyl-2-oxo-4-phenyl-2H-1-benzopyranas colorless crystals.

Melting point: 123°-125° C. (recrystallized from isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 0.95 (3H, t, J=7 Hz), 2.21 (3H, s.), 2.71 (1H, d,J=17.8 Hz), 3.23 (1H, d, J=17.8 Hz), 3.73 (3H, s), 3.97 (2H, m), 5.04(1H, s), 6.63 (1H, bs), 7.0-7.2 (4H, m), 7.3-7.4 (3H, m)

Elemental analysis (for C₂₂ H₂₂ O₆):

Calculated (%): C, 69.10; H, 5.80

Found (%): C, 68.77; H, 5.87

Process 3:

The compound obtained in Process 2 was reacted in substantially the samemanner as in Process 3 of Reference Example 13 to yield a mixture of thetrans and cis configurations of the title compound (trans:cis=about2.5:1 mixture) as colorless crystals.

Melting point: 152°-154° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.19 (3H, s), 2.55 (2H, m), 3.36 (1H,m), 4.27 (1H, d, J=12.6 Hz), 6.44 (1H, brs), 7.0-7.5 (7H, m), 2.27 (3H,s), 2.34 (1H, dd, J=17.8 Hz, J=7.6 Hz), 2.86 (1H, dd, J=18.0 Hz, J=6.6Hz), 3.50 (1H, m), 4.27 (1H, d, J=6.8 Hz), 7.0-7.5 (8H, m)

Elemental analysis (for C₁₈ H₁₆ O₄):

Calculated (%): C, 72.96; H, 5.44

Found (%): C, 72.94; H, 5.59

Reference Example 153,4-cis-6-Chloro-1,2,3,4-tetrahydro-1-methyl-4-phenyl-3-quinolineaceticacid

Process 1:

6-Chloro-4-phenyl-3-quinolinecarboxylic acid ethyl ester was reacted insubstantially the same manner as in Process 1 of Reference Example 5 toyield 6-chloro-1,4-dihydro-4-phenyl-3-quinolinecarboxylic acid ethylester as colorless crystals.

Melting point: 167°-168° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.18 (3H, t, J=7.1 Hz), 4.00-4.20 (2H,m), 5.08 (1H, s), 6.44 (1H, bd, J=6.2 Hz), 6.65 (1H, d, J=9.4 Hz),7.00-7.30 (7H, m), 7.54 (1H, d, J=6.2 Hz)

Elemental analysis (for C₁₈ H₁₆ NO₂ Cl):

Calculated (%): C, 68.90; H, 5.14; N, 4.46

Found (%): C, 68.66; H, 5.23; N, 4.56

Process 2:

The compound obtained in Process 1 was reacted in substantially the samemanner as in Process 2 of Reference Example 5 to yield6-chloro-1,4-dihydro-1-methyl-4-phenyl-3-quinolinecarboxylic acid ethylester as a colorless crystals.

Melting point: 159°-161° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 1MHz, CDCl₃) ppm: 1.19 (3H, t, J=7.1 Hz), 3.34 (3H, s),4.00-4.20 (2H, m), 5.08 (1H, s), 6.80 (1H, d, J=8.4 Hz), 7.05-7.30 (7H,m), 7.45 (1H, s)

Elemental analysis (for C₁₉ H₁₈ NO₂ Cl):

Calculated (%): C, 69.62; H, 5.53; N, 4.27

Found (%): C, 69.60; H, 5.54; N, 4.44

Process 3:

The compound obtained in Process 2 was reacted in substantially the samemanner as in Process 3 of Reference Example 5 to yield6-chloro-1,2,3,4-tetrahydro-1-methyl-4-phenyl-3-quinolinecarboxylic acidethyl ester as a mixture of stereo isomers. From this mixture, the3,4-cis isomer was obtained as colorless crystals.

Melting point: 138°-139° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.20 (3H, t, J=7.1 Hz), 3.01 (3H, s),3.10-3.55 (3H, m), 4.06 (2H, q, J=7.1 Hz), 4.52 (1H, d, J=5.6 Hz), 6.62(1H, d, J=9.0 Hz), 6.85-7.30 (7H, m)

Elemental analysis (for C₁₉ H₂₀ NO₂ Cl):

Calculated (%): C, 69.19; H, 6.11; N,4.25

Found (%): C, 68.94; H, 5.84; N, 4.22

Process 4:

To a suspension of lithium aluminum hydride (2.0 g) in THF (50 ml) wasadded dropwise a solution of the compound (cis isomer) obtained inProcess 3 (4.85 g) in THF (25 ml) at room temperature, followed bystirring at room temperature for 15 minutes. Water (2 ml) was added,followed by stirring for 15 more minutes. After the insoluble materialwas filtered off, the filtrate was concentrated. After ethyl acetate wasadded, the residue was washed with water and dried, after which thesolvent was distilled off, to yield3,4-cis-6-chloro-1,2,3,4-tetrahydro-3-hydroxymethyl-1-methyl-4-phenylquinolineas colorless crystals (3.91 g).

Melting point: 108°-110° C. (recrystallized from ethyl ether-hexane) NMR(200 MHz, CDCl₃) ppm: 2.41 (1H, m), 2.99 (3H, s), 3.00-3.22 (2H, m),3.27 (1H, dd, J=11.0, 7.2 Hz), 3.49 (1H, dd, J=11.0, 7.0 Hz), 4.20 (1H,d, J=5.2 Hz), 6.61 (1H, d, J=8.8 Hz), 6.86 (1H, d, J=2.4 Hz), 7.00-7.35(6H, m)

Elemental analysis (for C₁₇ H₁₈ NOCl):

Calculated (%): C, 70.95; H, 6.30; N, 4.87

Found (%): C, 70.52; H, 6.48; N, 5.08

Process 5:

The compound obtained in Process 4 was reacted in substantially the samemanner as in Process 2 of Reference Example 18 to yield3,4-cis-6-chloro-3-cyanomethyl-1,2,3,4-tetrahydro-1-methyl-4-phenylquinolineas colorless crystals.

Melting point: 166°-168° C. (recrystallized from ethyl ether-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.03 (1H, dd, J=17.0, 8.4 Hz), 2.14(1H, dd, J=17.0, 7.2 Hz), 2.61 (1H, m), 3.00 (3H, s), 3.05-3.40 (2H, m),4.23 (1H, d, J=5.0 Hz), 6.62 (1H, d, J=8.8 Hz), 6.86 (1H, d, J=1.8 Hz),7.00-7.40 (6H, m)

Elemental analysis (for C₁₈ H₁₇ N₂ Cl):

Calculated (%): C, 72.84; H, 5.77; N, 9.44

Found (%): C, 72.49; H, 5.79; N, 9.23

Process 6:

The compound obtained in Process 5 was reacted in substantially the samemanner as in Process 3 of Reference Example 18 to yield the titlecompound as colorless crystals.

Melting point: 192°-195° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.96 (1H, dd, J=17.0, 8.0 Hz), 2.28(1H, dd, J=17.0, 6.6 Hz), 2.75 (1H, m), 2.98 (3H, s), 3.05-3.20 (2H, m),4.16 (1H, d, J=5.2 Hz), 6.61 (1H, d, J=8.8 Hz), 6.86 (1H, d, J=2.6 Hz),6.95-7.35 (6H, m)

Elemental analysis (for C₁₈ H₁₈ NO₂ Cl):

Calculated (%): C, 68.46; H, 5.75; N., 4.44

Found (%): C, 68.44; H, 5.96; N, 4.24

Reference Example 163,4-trans-1,2,3,4-Tetrahydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolineaceticacid

Process 1:

A mixture of 2-benzoyl-4,5-dimethylbenzoic acid (11.4 g), acetone (300ml), DMF (10 ml), potassium carbonate (6.83 g) and diethyl bromomalonate(12.84 g) was stirred at room temperature for 60 hours. After thesolvent was distilled off, ethyl acetate was added to the residue. Thismixture was washed with water and dried, after which the solvent wasdistilled off. To the residue were added acetic acid (180 ml) andhydrochloric acid (180 ml), followed by heating at 110° C. for 5 hours.After the reaction mixture was concentrated, water was added to theconcentrate, followed by extraction with ethyl acetate. The extract waswashed with water and then dried, after which the solvent was distilledoff, to yield colorless crystals, which were recrystallized from ethylacetate-isopropyl ether, to yield6,7-dimethyl-1-oxo-4-phenyl-1H-2-benzopyran-3-carboxylic acid.

Melting point: 265°-268° C.

Process 2:

To a solution of the compound obtained in Process 1 (3.75 g) in methanol(50 ml) was added a 40% methylamine-methanol solution (25 ml), followedby stirring at room temperature for 2 hours. After the solvent wasdistilled off, 4N-HCl-ethyl acetate (50 ml) was added to the residue,followed by stirring at room temperature for 2 hours. After the solventwas distilled off, water was added to the residue, the precipitatedcrystals were collected by filtration and washed with water, acetone andethyl ether, to yield4-phenyl-2,6,7-trimethyl-1(2H)-isoquinolinone-3-carboxylic acid ascolorless crystals (3.51g).

Melting point: >300° C. (recrystallized from ethanol) NMR (200 MHz,CDCl₃ +DMSO-d₆) ppm: 2.25 (3H, s), 2.39 (3H, s), 3.67 (3H, s), 6.91 (1H,s), 7.39-7.42 (5H, m), 8,24 (1H, s)

Elemental analysis (for C₁₉ H₁₇ NO₃):

Calculated (%): C, 74.25; H, 5.58; N, 4.56

Found (%): C, 74.40; H, 5.50; N, 4.41

Process 3:

To a solution of the compound obtained in Process 2 (3.2 g) in DMF (30ml) was added sodium hydride (60% in oil) (0.50 g) while stirring thesolution, followed by addition of ethyl iodide (1.5 ml) and stirring atroom temperature for 16 hours. After the reaction mixture wasconcentrated, ethyl acetate was added to the concentrate. This mixturewas washed with water, after which the solvent was distilled off, toyield 2,6,7-trimethyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylic acidethyl ester as colorless crystals (3.3 g).

Melting point: 151°-153° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 0.92 (3H, t, J=7.2 Hz), 2.26 (3H, s),2.40 (3H, s), 3.61 (3H, s), 4.01 (2H, q, J=7.2 Hz), 6.96 (1H, s),7.30-7.46 (1H, m), 8.27 (1H, s)

Elemental analysis (for C₂₁ H₂₁ NO₃):

Calculated (%): C, 75.20; H, 6.31; N, 4.18

Found (%): C, 74.91; H, 6.29; N, 4.13

Process 4:

The compound obtained in Process 3 (1.0 g) was reacted in substantiallythe same manner as in Process 2 of Reference Example 2 to yield3,4-cis-1,2,3,4-tetrahydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinecarboxylicacid ethyl ester as colorless crystals (730 mg).

NMR (200 MHz, CDCl₃) ppm: 0.94 (3H, t, J=7.2 Hz), 2.17 (3H, s), 2.29(3H, s), 3.09 (3H, s), 3.72-4.02 (2H, m), 4.24 (1H, d, J=7.0 Hz), 4.84(1H, d, J=7.0 Hz), 6.72 (1H, s), 7.24-7.38 (5H, m), 7.98 (1H, s)

Process 5:

The compound obtained in Process 4 (690 mg) was reacted in substantiallythe same manner as in Process 3 of Reference Example 2 to yield3,4-trans-1,2,3,4-tetrahydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinecarboxylic acid as colorless crystals (610 mg).

Melting point: 248°-250° C. (recrystallized from ethyl acetate-ethylether) NMR (200 MHz, CDCl₃) ppm: 2.22 (3H, s), 2.28 (3H, s), 2.99 (3H,s), 4.22 (1H, s), 4.61 (1H, s), 6.89 (1H, s), 7.05-7.25 (5H, m), 7.94(1H, s)

Elemental analysis (for C₁₉ H₁₉ NO₃ ·1/5H₂ O):

Calculated (%): C, 72.92; H, 6.25; N, 4.48

Found (%): C, 72.84; H, 6.31; N, 4.42

Process 6:

The compound obtained in Process 5 was reacted in substantially the samemanner as in Process 1 of Reference Example 18 to yield3,4-trans-1,2,3,4-tetrahydro-3-hydroxymethyl-2,6,7-trimethyl-1-oxo-4-phenylisoquinolineas colorless crystals.

Melting point: 180°-182° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.23 (3H, s), 2.29 (3H, s), 3.03 (3H,s), 3.63 (1H, s), 3.55-3.75 (1H, m), 3.80-3.85 (1H, m), 4.27 (1H, s),6.92 (1H, s), 7.02-7.25 (5H, m), 7.88 (1H, s)

Elemental analysis (for C₁₉ H₂₁ NO₂):

Calculated (%): C, 77.26; H, 7.17; N, 4.74

Found (%): C, 77.02; H, 7.27; N, 4.66

Process 7:

The compound obtained in Process 6 was reacted in substantially the samemanner as in Process 2 of Reference Example 18 to yield3,4-trans-3-cyanomethyl-1,2,3,4-tetrahydro-2,6,7-trimethyl-1-oxo-4-phenylisoquinoIineas colorless crystals.

Melting point: 183°-184° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.27 (3H, s), 2.33 (3H, s), 2.56 (1H,dd, J=17.0, 9.2 Hz), 2.74 (1H, dd, J=17.0, 5.4 Hz), 3.01 (3H, s),3.85-3.98 (1H, m), 4.23 (1H, s like), 6.98 (1H, s), 7.00-7.05 (2H, m),7.20-7.30 (3H, m), 7.93 (1H, s)

Elemental analysis (for C₂₀ H₂₀ N₂ O):

Calculated (%): C, 78.92; H, 6.62; N, 9.20

Found (%): C, 79.08; H, 6.58; N, 9.35

Process 8:

The compound obtained in Process 7 was reacted in substantially the samemanner as in Process 3 of Reference Example 18 to yield the titlecompound as colorless crystals.

Melting point: 225°-227° C. (recrystallized from THF-isopropyl ether)NMR (200 MHz, CDCl₃) ppm: 2.25 (3H, s), 2.32 (3H, s), 2.65 (1H, dd,J=16.0, 8.8 Hz), 2.76 (1H, dd, J=16.0, 5.0 Hz), 2.97 (3H, s), 4.00-4.12(1H, m), 4.15 (1H, s like), 6.93 (1H, s), 6.95-7.10 (2H, m), 7.15-7.30(3H, m), 7.93 (1H, s)

Elemental analysis (for C₂₀ H₂₁ NO₃):

Calculated (%): C, 74.28; H, 6.55; N, 4.33

Found (%): C, 74.24; H, 6.49; N, 4.59

Reference Example 176-Chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinoxalineaceticacid

Process 1:

6-Chloro-1,2,3,4-tetrahydro-2-oxo-4-phenylquinoxalineN-(4-chlorophenyl)-1,2-phenylenediamine was chloroacetylated withchloroacetyl chloride, after which it was thermally reacted withpotassium carbonate in DMF in the presence of sodium iodide: Meltingpoint: 210°-212° C. (recrystallized from ethyl acetate-isopropyl ether):NMR (200 MHz, CDCl₃) ppm: 4.26 (2H, s), 6.75-6.85 (3H, m), 7.10-7.25(3H, m), 7.35-7.50 (2H, m), 9.26 (1H, bs)!

To a solution of this compound (4.70 g) in DMF (50 ml) was added sodiumhydride (60% in oil) (0.89 g), followed by stirring at room temperaturefor 30 minutes. After the mixture was cooled to 0° C., methyl iodide (5ml) was added, followed by stirring at room temperature overnight. Afterdilute hydrochloric acid was added, the mixture was extracted with ethylacetate. The extract was washed with water and dried, after which thesolvent was distilled off, to yield6-chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenylquinoxaline ascolorless crystals (1.88 g).

Melting point: 112°-114° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 3.42 (3H, s), 4.25 (2H, s), 6.84-7.00(3H, m), 7.13-7.25 (3H, m), 7.35-7.50 (2H, m)

Elemental analysis (for C₁₅ H₁₃ N₂ OCl):

Calculated (%): C, 66.06; H, 4.80; N, 10.27

Found (%): C, 66.21; H, 4.62; N, 10.44

Process 2:

While stirring a solution of the compound obtained in Process 1 (1.8 g)in THF (40 ml) at -78° C. in an argon atmosphere, a solution of 2Mlithium diisopropylamide in THF-heptane (5 ml) was added dropwise. Afterthe mixture was stirred for 30 minutes, a solution oft-butylbromoacetate (1.4 ml) in THF (5 ml) was added dropwise, followed bystirring at -78° C. for further 30 minutes. After saturated aqueousammonium chloride was added, the mixture was extracted with ethylacetate. The extract was washed successively with aqueous potassiumhydrogen sulfate, aqueous potassium carbonate and water and then dried,after which the solvent was distilled off, to yield6-chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinoxalineaceticacid t-butyl ester as a pale yellow oily substance. To this oilysubstance were added a 3N aqueous sodium hydroxide solution (10 ml) andmethanol (40 ml), followed by heating under reflux for 2 hours. Afterthe solvent was distilled off, water was added to the residue, which waswashed with ether. The water layer was weakly acidified with dilutehydrochloric acid and then extracted with ethyl acetate. The extract waswashed with water and dried, after which the solvent was distilled off,to yield the title compound as colorless crystals (1.03 g).

Melting point: 152°-153° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.69 (2H, d, J=6.6 Hz), 3.42 (3H, s),4.60-5.80 (1H, bs), 4.93 (1H, t, J=6.6 Hz), 6.88 (1H, s like), 6.97 (2H,s like), 7.10-7.40 (5H, m)

Elemental analysis (for C₁₇ H₁₅ N_(O) ₃ Cl):

Calculated (%): C, 61.73; H, 4.57; N, 8.47

Found (%): C, 61.96; H, 4.61; N, 8.75

Reference Example 186-Chloro-1,2-dihydro-1-methyl-2-oxo-4-phenyl-3-quinolineacetic acid

Process 1:

To a solution of6-chloro-1,2-dihydro-1-methyl-2-oxo-4-phenyl-3-quinolinecarboxylic acid(4.41 g) in anhydrous THF (50 ml) were added oxalyl chloride (1.83 ml)and DMF (one drop), followed by stirring at room temperature for 1.5hours. Upon solvent removal by distillation, the acid chloride wasobtained as colorless crystals (4.60 g). To a solution of this acidchloride (4.0 g) in THF (65 ml) was added sodium borohydride (NaBH₄)(1.30 g) at room temperature, followed by stirring for 0.5 hours. Thento this solution was added 1,2-dimethoxyethane (50 ml) and then NaBH₄(0.30 g), followed by stirring at 50° C. for 1 hour. Then, NaBH₄ (0.20g) was added to the solution, followed by stirring at the roomtemperature for 1 hour. The separated precipitate was filtered off, andthe flitrate was added to a dilute hydrochloric acid solution undercooling conditions, followed by extraction with ethyl acetate. Theextract was washed with water and dried, after which the solvent wasdistilled off. The residue was purified by silica gel colnmnchromatography (hexane:ethyl acetate=2:1→1:1) to yield6-chloro-1,2-dihydro-3-hydroxymethyl-1-methyl-2-oxo-4-phenylquinoline ascolorless crystals (1.90 g).

Melting point: 141°-142° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 3.81 (3H, s), 3.96 (1H, b), 4.40 (2H,s), 7.17 (1H, d, J=2.4 Hz), 7.23-7.27 (2H, m), 7.38 (1H, d, J=9.2 Hz),7.49-7.54 (4H, m)

Elemental analysis (for C₁₇ H₁₅ NO₂ Cl):

Calculated (%): C, 67.89; H, 5.03; N, 4.66

Found (%): C, 67.63; H, 4.79; N, 4.55

Process 2:

While stirring a solution of 3-hydroxymethyl derivative obtained inProcess 1 (1.80 g) in dichloromethane (45 ml) at 0° C., triethylamine(1.08 ml) and methanesulfonyl chloride (0.61 ml) were added, followed bystirring at for 1 hour. The reaction mixture was concentrated, and ethylacetate was added to the residue. This mixture was washed with water anddried, after which the solvent was distilled off, to yield6-chloro-1,2-dihydro-3-methanesulfonyloxymethyl-1-methyl-2-oxo-4-phenylquinolineas colorless crystals (2.0 g) NMR (200 MHz, CDCl₃) ppm: 3.14 (3H, s),3.81 (3H, s), 5.00 (2H, s), 7.17-7.58 (8H, m)!.

Without purification, this compound was dissolved in DMSO (20 ml), andsodium cyanide (2.0 g) was added, followed by stirring at roomtemperature for 1 hour. To this reaction mixture was added ethylacetate, and the resulting mixture was washed with water and dried,after which the solvent was distilled off, to yield6-chloro-3-cyanomethyl-1,2-dihydro-1-methyl-2-oxo-4-phenylquinoline ascolorless crystals (1.43 g).

Melting point: 160°-161° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 3.47 (2H, s), 3.84 (3H, s), 7.12 (1H,d, J=3.0 Hz), 7.21-7.31 (2H, m), 7.39 (1H, d, J=9.0 Hz), 7.53-7.61 (4H,m)

Elemental analysis (for C₁₈ H₁₃ N₂ OCl):

Calculated (%): C, 70.02; H, 4.24; N, 9.07

Found (%): C, 69.75; H, 4.36; N, 8.81

Process 3:

A mixture of the compound obtained in Process 2 (1.10 g), acetic acid(10 ml) and hydrochloric acid (10 ml) was heated at 110° C. for 2 hours.After the solvent was distilled off, ethyl acetate was added to theresidue. The mixture was washed with water and dried, after which thesolvent was distilled off, to yield the title compound as colorlesscrystals (1.06 g).

Melting point: 195°-199° C. (recrystallized from ethyl acetate-ethylether) NMR (200 MHz, CDCl₃) ppm: 3.50 (2H, s), 3.89 (3H, s), 7.18-7.59(8H, m)

Elemental analysis (for C₁₈ H₁₄ NO₃ Cl):

Calculated (%): C, 65.96; H, 4.31; N, 4.27

Found (%): C, 65.75; H, 4.34; N, 4.15

Reference Example 19

1,2-Dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolineaceticacid

The isoquinoline-3-carboxylic acid obtained in Process 2 of ReferenceExample 16 was reacted in substantially the same manner as in Process 1and 2 of Reference Example 21 to yield the title compound as colorlesscrystals.

Melting point: 217°-220° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.22 (3H, s), 2.37 (3H, s), 3.63 (2H,s), 3.67 (3H, s), 5.90 (1H, brs), 6.75 (1H, s), 7.20-7.35 (2H, m),7.40-7.55 (3H, m), 8.24 (1H, s)

Elemental analysis (for C₂₀ H₁₉ NO₃):

Calculated (%): C, 74.75; H, 5.96; N, 4.36

Found (%): C, 74.69; H, 6.08; N, 4.23

Reference Example 20 6-Chloro-1-oxo-4-phenyl-1H-2-benzopyran-3-aceticacid

Process 1:

6-Chloro-1-oxo-4-phenyl-1H-2-benzopyran-3-carboxylic acid was reacted insubstantially the same manner as in Process 1 of Reference Example 18 toyield 6-chloro-3-hydroxymethyl-1-oxo-4-phenyl-1H-2-benzopyran ascolorless crystals.

Melting point: 161°-164° C. (recrystallized from ethyl acetate-ethylether) NMR (200 MHz, CDCl₃) ppm: 2.20 (1H, b), 4.30 (2H, s), 7.05 (1H,d, J=2.2 Hz), 7.28-7.53 (1H, d, J=2.0 Hz), 8.30 (1H, d, J=8.6 Hz)

Elemental analysis (for C₁₆ H₁₁ O₃ Cl):

Calculated (%): C, 67.03; H, 3.87

Found (%): C, 66.85; H, 3.95

Process 2:

The compound obtained in Process 1 was reacted with methanesulfonylchloride in the same manner as the reaction in Process 2 of ReferenceExample 18 to yield6-chloro-3-methanesulfonyloxymethyl-1-oxo-4-phenyl-1H-2-benzopyran ascolorless crystals.

Melting point: 179°-180° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 3.10 (3H, s), 4.86 (2H, s), 7.08 (1H,d, J=2.0 Hz), 7.30-7.34 (2H, m), 7.53-7.58 (4H, m), 8.33 (1H, d, J=8.4Hz)

Elemental analysis (for C₁₇ H₁₃ O₅ ClS):

Calculated (%): C, 55.97; H, 3.59

Found (%): C, 55.69; H, 3.79

Process 3:

The compound obtained in Process 2 was reacted with sodium cyanide inthe same manner as the reaction in Process 2 of Reference Example 18 toyield 6-chloro-3-cyanomethyl-1-oxo-4-phenyl-1H-2-benzopyran as a paleyellow oily substance.

NMR (200 MHz, CDCl₃) ppm: 3.45 (2H, s), 7.01 (1H, d, J=2.2 Hz),7.29-7.60 (6H, m),8.31(1H, d, J=8.6 Hz)

Process 4:

The compound obtained in Process 3 was reacted in the same manner as inProcess 3 of Reference Example 18 to yield the title. compound ascolorless crystals.

Melting point: 211°-215° C. (recrystallized from ethyl acetate-ethylether) NMR (200 MHz, CDCl₃) ppm: 3.46 (2H, s), 6.99 (1H, d, J=2.0 Hz),7.28-7.56 (6H, m), 8.28 (1H, d, J=8.4 Hz)

Elemental analysis (for C₁₇ H₁₁ O₄ Cl·1/4H₂ O):

Calculated (%): C, 63.96; H, 3.63

Found (%): C, 64.09; H, 3.64

Reference Example 21 6-Chloro-2-oxo-4-phenyl-2H-1-benzopyran-3-aceticacid

Process 1:

To a solution of 6-chloro-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylicacid (6.1 g) in anhydrous THF (100 ml) were added oxalyl chloride (2.7ml) and DMF (several drops), followed by stirring at room temperaturefor 3 hours. Upon solvent removal by distillation, an acid chloride wasobtained as colorless crystals. To a solution of this acid chloride inanhydrous THF (100 ml) was added a solution of diazomethane in ethylether (prepared from 12.0 g of N-nitrosomethyleurea), followed bystirring at room temperature for 0.5 hours. Upon solvent removal bydistillation, a diazoketone derivative was obtained as an oily substanceNMR (200 MHz, CDCl₃) ppm: 5.4 (1H, bs), 7.19 (1H, d, J=2.2 Hz), 7.3-7.4(3H, m), 7.5-7.6 (4H, m); IRv_(max) (Neat)cm⁻¹ : 2100, 1720, 1620!.

This diazoketone derivative was dissolved in methanol (300 ml). Whilestirring this solution with heating at 50° C., silver oxide (Ag₂ O) (3.0g) was added portionwise. After this mixture was stirred for 3 hourswith heating under reflux, it was filtered through Celite, and theflitrate was distilled to remove the solvent. The residue wasfractionated and purified by silica gel column chromatography(hexane:ethyl acetate=3:1) to yield6-chloro-2-oxo-4-phenyl-2H-1-benzopyran-3-acetic acid ethyl ester as anorange oily substance (4.14 g). This oily substance becomes colorlesscrystals upon addition of ethyl acetate-hexane.

Melting point: 98°-99° C. (recrystallized from ethyl acetate-hexane) NMR(200 MHz, CDCl₃) ppm: 3.40 (2H, s), 3.68 (3H, s), 6.99 (1H, d, J=2.2Hz), 7.2-7.6 (7H, m)

Elemental analysis (for C₁₈ H₁₃ O₄ Cl):

Calculated (%): C, 65.76; H, 3.99

Found (%): C, 65.92; H, 3.84

Process 2:

A mixture of the crude compound obtained in Process 1 (4.1 g), aceticacid (48 ml) and hydrochloric acid (24 ml) was heated under reflux for 1hour. After the solvent was distilled off, ethyl acetate was added tothe residue. This mixture was washed with water and dried, after whichthe solvent was distilled off, followed by treatment of the residue withisopropyl ether, to yield the title compound as pale yellow crystals(2.32 g).

Melting point: 174°-177° C. (recrystallized from isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 3.44 (2H, s), 7.01 (1H, d, J=2.4 Hz), 7.2-7.6 (7H,m)

Elemental analysis (for C₁₇ H₁₁ O₄ Cl):

Calculated (%): C, 64.88; H, 3.52

Found (%): C, 65.13; H, 3.54

Reference Example 22 6-Methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-aceticacid

Process 1:

A mixture of 6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylic acidethyl ester prepared by heating 2-hydroxy-5-methylbenzophenone anddiethyl malonate in the presence of 1,8-diazabicyclo 5.4.0!undec-7-en;melting point: 129°-131° C.; NMR (200 MHz, CDCl₃) ppm: 0.96 (3H, t,J=7.2 Hz), 2.31 (3H, s), 4.07 (2H, q, J=7.2 Hz), 7.01 (1H, bs), 7.2-7.4(4H, m), 7.5-7.6 (3H, m)! (10.0 g), acetic acid (100 ml). andhydrochloric acid (60 ml) was heated under reflux at 110° C. for 15hours. After the solvent was distilled off, ethyl acetate was added tothe residue. The mixture was washed with water and dried, after whichthe solvent was distilled off, to yield6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylic acid as colorlesscrystals (8.7 g).

Melting point: 260°-262° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.31 (3H, s), 6.95 (1H, bs), 7.2-7.3(2H, m), 7.39 (H, d, J=8.6 Hz), 7.5-7.6 (4H, m)

Elemental analysis (for C₁₇ H₁₂ O₄):

Calculated (%): C, 72.85; H, 4.32

Found (%): C, 73.13;.H, 4.45

Process 2:

The compound obtained in Process 1 was reacted in substantially the samemanner as in Process 1 of Reference Example 21 to yield6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-acetic acid methyl ester ascolorless crystals.

Melting point: 142°-144° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.72 (3H, s), 3.39 (2H, s), 3.67 (3H,s), 6.79 (1H, brs), 7.2-7.3 (4H, m), 7.5-7.6 (3H, m)

Elemental analysis (for C₁₉ H₁₆ O₄):

Calculated (%): C, 74.01; H, 5.23

Found (%): C, 73.75; H, 5.23

Process 3:

The compound obtained in Process 2 was reacted in substantially the samemanner as in Process 2 of Reference Example 21 to yield the titlecompound as colorless crystals.

Melting point: 214°-217° C. (recrystallized from chloroform-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.27 (3H, s), 3.42 (2H, s), 6.80 (1H,brs), 7.2-7.3 (4H, m), 7.5-7.6 (3H, m)

Elemental analysis (for C₁₈ H₁₄ O₄):

Calculated (%): C, 73.46; H, 4.79

Found (%): C, 73.37; H, 4.79

Reference Example 23 6-Chloro-4-phenyl-3-quinolineacetic acid

Process 1:

While stirring a mixture of 6-chloro-4-phenyl-3-quinolinecarboxylic acidmethyl ester (8.0 g) and ethyl ether (100 ml) at 0° C., lithium aluminumhydride (1.0 g) was added, followed by stirring for 30 minutes. Afterwater (5 ml) was added, the mixture was stirred at room temperature for30 more minutes. After ethyl acetate was added; the insoluble materialwas filtered off. The flitrate was washed by successively with aqueouspotassium carbonate and saturated aqueous sodium chloride and thendried, after which the solvent was distilled off, to yield6-chloro-3-hydroxymethyl-4-phenylquinoline as colorless crystals (6.05g).

Melting point: 169°-170° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 4.63 (2H, s), 7.20-7.35 (2H, m),7.40-7.65 (5H, m), 8.07 (1H, d, J=8.8 Hz), 9.09 (1H, s)

Elemental analysis (for C₁₆ H₁₂ NOCl):

Calculated (%): C, 71.25; H, 4.48; N, 5.19

Found (%): C, 71.44; H, 4.51; N, 5.30

Process 2:

The compound obtained in Process 1 was reacted in substantially the samemanner as in Process 2 of Reference Example 18 to yield6-chloro-3-cyanomethyl-4-phenylquinoline as colorless crystals.

Melting point: 149°-151° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 3.65 (2H, s), 7.25-7.35 (2H, m), 7.43(1H, d, J=2.2 Hz), 7.58-7.75 (4H, m), 8.12 (1H, d, J=9.0 Hz), 9.04 (1H,s)

Elemental analysis (for C₁₇ H₁₁ N₂ Cl):

Calculated (%): C, 73.25; H, 3.98; N, 10.05

Found (%): C, 72.86; H, 8.98; N, 10.86

Process 3:

The compound obtained in Process 2 was reacted in substantially the samemanner as in Process 3 of Reference Example 18 to yield the titlecompound as colorless crystals.

Melting point: 211°-213° C. (recrystallized fromtetrahydrofuran-isopropyl ether)

NMR (200 MHz, CDCl₃) ppm: 3.61 (2H, s), 4.10 (1H, bs), 7.25-7.85 (2H,m), 7.43 (1H, d, J=2.2 Hz), 7.50-7.70 (4H, m), 8.19 (1H, d, J=8.8 Hz),8.95 (1H, s)

Elemental analysis (for C₁₇ H₁₂ NO₂ Cl·0.8H₂ O):

Calculated (%): C, 65.41; H, 4.89; N, 4.49

Found (%): C, 65.42; l=I, 4.16; N, 4.66

Reference Example 24

4-(2-Methoxyphenyl)-1-oxo-1H-2-benzopyran-3-acetic acid

4-(2-Methoxyphenyl)-1-oxo-1H-2-benzopyran-3-carboxylic acid was reactedin substantially the same manner as in Process 1 and 2 of ReferenceExample 21 to yield the title compound as colorless crystals.

Melting point: 148°-144° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 3.44 (2H, s), 3.72 (3H, s), 6.9-7.6(7H, m), 8.34 (1H, m)

Reference Example 256-Chloro-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid

Process 1:

A mixture of 5-Chloro-2-hydroxy-2'-methylbenzophenone prepared byreaction of 4-chloroanisole with ortho-toluoyl chloride in1,1,2,2,-tetrachloroethane in the presence of aluminum chloride (150°C., 7 hours): melting point 65°-66° C.!(71.9g), diethyl malonate (70 ml)and 1,8-diazabicyclo 5.4.0!undec-7-ene (4 ml) was stirred at 170° C. for6 hours. The reaction mixture was purified by silica gel columnchromatography (hexane) to yield6-chloro-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-carboxylic acidethyl ester as colorless crystals (73.2 g).

Melting point: 93°-95° C. (recrystallized from isopropyl ether-hexane)

Process 2:

The compound obtained in Process 1 was reacted by a method similar toProcess 1 of Reference Example 22 to yield the title compound ascolorless crystals.

Melting point: 211°-214° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.09 (3H, s), 6.9-7.1 (2H, m), 7.3-7.5(4H, m), 7.64 (1H, dd, J=8.8, 2.2 Hz)

Reference Example 266-Chloro-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-acetic acid

The compound obtained in Reference Example 25 was reacted by a methodsimilar to Process 1 of Reference Example 21 to yield the methyl esterof the title compound as an oil.

NMR (200 MHz, CDCl3) ppm: 2.09 (3H, s), 3.24 (1H, d, J=16.5 Hz), 3.43(1H, d, J=16.5 Hz), 3.66 (3H, s), 6.83 (1H, d, J=2.2 Hz), 7.10 (1H, m),7.3-7.5 (5H, m)!

This compound was reacted by a method similar to Process 2 of ReferenceExample 21 to yield the title compound as colorless crystals.

Melting point: 180°-183° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.05 (3H, s), 3.27 (1H, d, J=16.8 Hz),3.45 (1H, d, J=16.8 Hz), 6.83 (1H, d, J=2.2 Hz), 7.10 (1H, d, J=6.6 Hz),7.3-7.5 (5H, m)

Reference Example 276-Chloro-4-(2-methoxyphenyl)-2-oxo-2H-1-benzopyran-3-acetic acid

Process 1:

A mixture of 5-chloro-2-hydroxy-2'-methoxybenzophenone prepared from2-bromo-4-chloro-(2-methoxyethoxy)methoxybenzene and orthoanisaldehydeas the starting materials: melting point, 94°-98° C. (recrystallizedfrom isopropyl ether)!(11.8 g), diethyl malonate (13.6 g) and potassiumfluoride (2.61 g) was heated at 180° C. for 8.5 hours. After cooling,ethyl acetate was added to the mixture, washed with water, dried andevaporated. The residue was subjected to silica gel columnchromatography (ethyl acetate:hexane: 1:10) to yield6-chloro-4-(2-methoxyphenyl)-2-oxo-2H-1-benzopyran-3-carboxylic acidethyl ester as colorless crystals (7.78 g).

Melting point: 108°-109° C. (recrystallized from ethyl acetate-ethylether)

Process 2:

The compound obtained in Process 1 was subjected to hydrolysis by amethod similar to Process 2 of Reference Example 25 to yield6-chloro-4-(2-methoxyphenyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid ascolorless crystals.

Melting point: 197°-199° C. (recrystallized from ethyl acetate-methanol)

Process 3:

The compound obtained in Process 2 was subjected to carbon-elongation bya method similar to Process 1 of Reference Example 26 to yield6-chloro-4-(2-methoxyphenyl)-2-oxo-2H-1-benzopyran-3-acetic acid methylester as colorless crystals.

Melting point: 182°-183° C. (recrystallized from ethyl acetate)

Process 4:

The compound obtained in Process 3 was subjected to hydrolysis by amethod similar to Process 2 of Reference Example 26 to yield the titlecompound as colorless crystals.

Melting point: 200°-202° C. (recrystallized from ethyl acetate)

Reference Example 28 6-Chloro-2-oxo-4-2-(trifluoromethyl)phenyl)-2H-1-benzopyran-3-acetic acid

Process 1:

5-Chloro-2-hydroxy-2'-(trifluoromethyl)benzophenone prepared from2-bromo-4-chloro-(2-methyoxyethoxy)methoxybenzene andortho-(trifluoromethyl)benzaldehyde as the starting materials: meltingpoint, 71°-72° C. (recrystallized from hexane-isopropyl ether)! wasreacted by a method similar to Process 1 of Reference Example 25 toyield 6-chloro-2-oxo-4-2-(trifluoromethyl)phenyl)-2H-1-benzopyran-3-carboxylic acid ethyl esteras an oily substance.

NMR (200 MHz, CDCl₃) ppm: 0.95 (3H, t, J=7.2Hz), 4.05 (2H, q, J=7.2 Hz),6.81 (1H, d, J=2.4 Hz), 7.30-7.38 (2H, m), 7.54 (1H, dd, J=2.6, 8.8 Hz),7.71 (2H, t, J=4.2 Hz), 7.82-7.90 (1H, m)

Process 2:

The compound obtained in Process 3 was reacted by a method similar toProcess 2 of Reference Example 25 to yield 6-chloro-2-oxo-4-2-(trifluoromethyl)phenyl)-2H-1-benzopyran-3-carboxylic acid ascolorless crystals.

Melting point: 205°-209° C. (recrystallized from ethyl acetate)

Process 3:

The compound obtained in Process 2 was subjected to carbon-elongation bya method similar to Process 1 of Reference Example 26 to yield6-chloro-2-oxo-4- 2-(trifluoromethyl)phenyl)-2H-1-benzopyran-3-aceticadd methyl ester as colorless crystals.

Melting point: 146°-147° C. (recrystallized from ethyl acetate)

Process 4:

The compound obtained in Process 3 was reacted by a method similar toProcess 2 of Reference Example 26 to yield the title compound ascolorless crystals.

Melting point: 167°-169° C. (recrystallized from isopropyl ether)

Reference Example 292,6,7-Trimethyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylic acid

Process 1:

A mixture of 2-benzoyl-4,5-dimethylbenzoic acid (11.4 g), acetone (300ml), DMF (10 ml), potassium carbonate (6.83 g) and diethyl bromomalonate(12.84 g) was stirred at room temperature for 60 hours. After thesolvent was distilled off, ethyl acetate was added to the residue. Thismixture was washed with water and then dried, after which the solventwas distilled off. To the residue were added acetic acid (180 ml) andhydrochloric acid (180 ml), followed by heating at 110° C. for 5 hours.The reaction mixture was concentrated, and water was adored to theconcentrate, followed by extraction with ethyl acetate. The extract waswashed with water and then dried, after which the solvent was distilledoff, to yield colorless crystals. The crystals were recrystallized fromethyl acetate-isopropyl ether to yield6,7-dimethyl-4-phenylisocoumarin-3-carboxylic acid(≡6,7-dimethyl-1-oxo-4-phenyl-1H-2-benzopyran-3-carboxylic acid).

Melting point: 265°-268° C.

Process 2:

To a solution of the compound (3.75 g) obtained in Process i in methanol(50 ml) was added a 40% methylamine-methanol solution (25 ml), followedby stirring at room temperature for 2 hours. After the solvent wasdistilled off, 4N-HCl-ethyl acetate (50 ml) was added to the residue,followed by stirring at room temperature for 2 hours. After the solventwas distilled off, water was added to the residue, and the precipitatedcrystals were collected by filtration and then washed with water,acetone and ethyl ether to yield the title compound as colorlesscrystals (3.51 g).

Melting point: >300° C. (recrystallized from ethanol) NMR (200 MHz,CDCl₃ +DMSO-d₆) ppm: 2.25 (3H, s), 2.39 (3H, s), 3.67 (3H, s), 6.91 (1H,s), 7.39-7.42 (5H, m), 8.24 (1H, s)

Elemental analysis (for C₁₉ H₁₇ NO₃):

Calculated: C, 74.25; H, 5.58; N, 4.56

Found: C, 74.40; H, 5.50; N, 4.41

The compound obtained in Process 1 of Reference Example 29 was reactedwith ethylamine, n-butylamine, N,N-dimethylaminoethylenediamine orammonia, in place of methylamine, in the same manner as in Process 2, toyield the compounds of Reference Examples 30 through 33 as colorlesscrystals.

Reference Example 302-Ethyl-6,7-dimethyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylic acid

Melting point: 254°-256° C. (recrystallized from ethyl acetate-methanol)

Reference Example 312-n-Butyl-6,7-dimethyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylic acid

Melting point: 218°-219° C. (recrystallized from ethyl acetate-isopropylether)

Reference Example 322-(2-Dimethylaminoethyl)-6,7-dimethyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylicacid

Melting point: 291°-293° C. (recrystallized from chloroform-methanol)

Reference Example 33

6,7-Dimethyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylic acid

Melting point: 325°-327° C. (recrystallized from chloroform-methanol)

Reference Example 344-(4-Fluorophenyl)-2,6,7-trimethyl-1(2H)-isoquinolinone-3-carboxylicacid

4,5-Dimethyl-2-(4-fluorobenzoyl)benzoic acid, in place of2-benzoyl-4,5-dimethylbenzoic acid, was reacted and treated in the samemanner as in Process 1 of Reference Example 29 to yield4-(2-fluorophenyl)-6,7-dimethylisocoumarin-3-carboxylic acid meltingpoint 214°-217° C. (recrystallized from ethyl acetate)!. This compoundwas reacted in the same manner as in Process 2 of Reference Example 29to yield the title compound as colorless crystals.

Melting point: 309°-312° C. (recrystallized from chloroform-methanol)

Reference Example 355-Fluoro-4-(4-fluorophenyl)-2-methyl-1(2H)-isoquinolinone-3-carboxylicacid

5-Fluoro-4-(4-fluorophenyl)isocoumarin-3-carboxylic acid and methylaminewere reacted in the same manner as in Process 2 of Reference Example 29to yield the title compound as colorless crystals.

Melting point: 256°-257° C. (recrystallized from acetone-isopropylether)

Reference Example 366,7-Dichloro-2-methyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylic acid

2-Benzoyl-4,5-dichlorobenzoic acid, in place of2-benzoyl-4,5-dimethyl-benzoic acid, was reacted and treated in the samemanner as in Process 1 of Reference Example 29 to yield6,7-dichloro-4-phenylisocoumarin-3-carboxylic acid melting point243°-244° C. (recrystallized from ethyl acetate-isopropyl ether)!. Thiscompound was reacted and treated in the same manner as in Process 2 ofReference Example 29 to yield the title compound as colorless crystals.

Melting point: >300° C. (recrystallized from chloroform-methanol)

Reference Example 37 2-2-(N,N-Dimethylamino)ethyl!-4-phenyl-1-(2H)-isoquinolinone-3-carboxylicacid

1-Oxo-4-phenyl-1H-2-benzopyran-3-carboxylic acid andN,N-dimethylaminoethylenediamine were reacted by a method similar toProcess 1 and 2 of Reference Example 29 to yield the title compound ascolorless crystals.

Melting point: 295°-296° C. (recrystallized from chloroformmethanol-dichloromethane-ethyl ether)

Reference Example 382,6,7-Trimethyl-4-(2-methylphenyl)-1(2H)-isoquinolinone-3-carboxylicacid

Process 1:

A mixture of 4,5-dimethyl-2-(2-methylbenzoyl)benzoic acid (7.7 g),dichloromethane (100 ml), oxalyl chloride (2.74 ml) and DMF (3 drops)was stirred at room temperature for 2 hours. After the solvent wasdistilled off, dichloromethane (50 ml) was added to the residue. Thismixture was added dropwise to a mixture of N-methylaminoacetonitrilehydrochloride (4.86 g), triethylamine (12.0 ml) and dichloromethane (70ml), while stirring with ice cooling. This mixture was stirred at roomtemperature for 12 hours. After the solvent was distilled off, ethylacetate was added to the residue. The mixture was washed successivelywith water, dilute hydrochloric acid, sodium hydrogen carbonate andwater and then dried, after which the solvent was distilled off, toyield 4,5-dimethyl-2-(2-methylbenzoyl)benzoicacid-N-cyanomethyl-N-methylamide as a colorless oily substance (9.2 g).NMR (200 MHz, CDCl₃) ppm: 2.26 (3H, s), 2.35 (3H, s), 2.37 (3H, s), 2.99(3H, s), 4.47 (2H, s), 7.05-7.40 (6H, m)

Process 2:

A mixture of the compound (9.1 g) obtained in Process 1, toluene (200ml) and 1,8-diazabicyclo 5.4.0!undec-7-ene (8 ml) was stirred for 7hours under refluxing. After ethyl acetate was added, the reactionmixture was washed successively with water, dilute hydrochloric acid,aqueous sodium hydrogen carbonate and water and then dried, after whichthe solvent was distilled off, to yield3-cyano-2,6,7-trimethyl-4-(2-methylphenyl)-1(2H)-isoquinolinone ascolorless crystals (6.3 g).

Melting point: 217°-218° C. (recrystallized from ethyl acetate)

Process 3:

The compound (5.8 g) obtained in Process 2, ethanol (20 ml) and 1Nsodium hydroxide (25 ml) were stirred for 3 hours under refluxing. Thereaction mixture was concentrated, dilute hydrochloric acid was added tothe concentrate, and the precipitated crystals were collected byfiltration. The crystals were washed with water, acetone and ethyl etherto yield2,6,7-trimethyl-4-(2-methylphenyl)-1(2H)-isoquinolinone-3-carboxylicacid amide as colorless crystals (6.1 g).

Melting point: 296°-299° C. (recrystallized from methanol)

Process 4:

To a mixture of the compound (1.0 g) obtained in Process 3, acetic acid(15 ml) and concentrate hydrochloric acid (30 ml) was added portionwisesodium nitrite (6.2 g) at room temperature, followed by stirring for 5hours. To the reaction mixture was added water, and the precipitatedcrystals were collected by filtration, which were then washed withwater, acetone and ethyl ether, to yield the title compound as colorlesscrystaIs (0.97 g).

Melting point: 291°-292.5° C. (recrystallized from ethyl acetate)

2-Benzoylbenzoic acids having respective corresponding substituents, inplace of 4,5-dimethyl-2-(2-methylbenzoyl)benzoic acid of Process 1 ofReference Example 38, were reacted and treated in the same manner as inprocesses 2 through 4 to yield the compounds of Reference Example 39 to45 as colorless crystals.

Reference Example 394-(2,6-Dimethylphenyl)-2-methyl-1(2H)-isoquinolinone-3-carboxylic acid

Melting point: 284°-285.5° C. (recrystallized from methanol-ethanol)

Reference Example 40

4-(4-Fluoro-2-methylphenyl)-2-methyl-1(2H)-isoquinolinone-3-carboxylicacid

Melting point: 257.5°-260° C. (recrystallized from ethylacetate-ethanol)

Reference Example 41

2-Methyl-4-(2-methylphenyl)-1(2H)-isoquinolinone-3-carboxylic acid

Melting point: 225°-227° C. (recrystallized from ethyl acetate-ethanol)

Reference Example 42

4-(2-Ethylphenyl)-2-methyl-1(2H-isoquinolinone-3-carboxylic acid

Melting point: 100°-102° C. 2/3 hydrate!(recrystallized from ethylacetate-isopropyl ether)

Reference Example 43

4-(2-Ethylphenyl)-2,6,7-trimethyl-1(2H)-isoquinolinone-3-carboxylic acid

Melting point: 214°-215° C. (recrystallized from ethyl acetate-ethanol)

Reference Example 444-(2,6-Dimethylphenyl)-2,6,7-trimethyl-1(2H)-isoquinolinone-3-carboxylicacid

Melting point: >300° C. (recrystallized from ethyl acetate-ethanol)

Reference Example 45 2-Methyl-4-2-(trifluoromethyl)phenyl!-1-(2H)-isoquinolinone-3-carboxylic acid

Melting point: 250°-253° C. (recrystallized from ethyl acetate-THF)

Reference Example 465,6,7,8-Tetrahydro-2-methyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylicacid

Process 1:

To a solution of 2-benzoyl-1-cyclohexenecarboxylic acid prepared from3,4,5,6-tetrahydrophtalic anhydride by reacting with aluminum chloiridein benzene! (7.05 g) in THF (100 ml) were added DMF (a few drops) andoxalyl chloride (3.20 ml) at room temperature, and the mixture wasstirred for 2 hours. The solvent was evaporated, and the residue wasdissolved in THF (50 ml). The solution was added dropwise to a stirredmixture of N-methylglycine ethyl ester hydrochloride (5.64 g), THF (100ml) and triethylamine (12.0 ml) at 0° C. The mixture was stirred at roomtemperature for 2 hours and under reflux for 4 hours, and the solventwas evaporated. To the residue was added ethyl acetate. The mixture waswashed successively with water, diluted hydrochloric acid, water,aqueous sodium hydrogen carbonate and water, dried, and the solvent wasevaporated to yield N-(2-benzoyl-1-cyclohexenecarbonyl)-N-methylglycineethyl ester as a paIe yellow oil (9.73 g). To the solution of thiscompound in THF (250 ml) was added pottasinm t-butoxide (3.97 g) at 0°C. with stirring, and the mixture was stirred for 10 minutes at roomtemperature. The solvent was evaporated, and to the residue was addedethyl acetate. The mixture was washed with water, dried and the solventwas evaporated to yield5,6,7,8-tetrahydro-2-methyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylicacid ethyl ester as colorless crystals (1.86 g).

Melting point: 131°-132° C. (recrystallized from isopropyl ether)

Process 2:

A mixture of the compound obtained in Process 1 (1.00 g), dioxane (20ml), and 1N-NaOH (20 ml) was refluxed for 2 hours. The solvent wasevaporated, and to the residue was added water. The mixture wasacidified with hydrochloric acid, and extracted with ethyl acetate. Theextract was washed with water, dried, and the solvent was evaporated toyield the title compound as colorless crystals (519 mg).

Melting point: 226°-227° C. (recrystallized from ethyl acetate-isopropylether)

Reference Example 47 1,2-Dihydro-3-hydroxymethyl-2,6,7-trimethyl-1-oxo-4-phenylisoquinoline

To a solution of the compound (9.27 g) obtained in Reference Example 29in THF (100 ml) were added oxalyl chloride (3.7 ml) and DMF (10 drops)at room temperature, followed by stirring for 30 minutes. After thesolvent was distilled off, the residue was dissolved in THF (50 ml).This solution was gradually added at 0° C. to a suspension of sodiumborohydride (5.0 g) in dimethoxyethane (100 ml). After stirring at 0° C.for 30 minutes, the reaction mixture was added to 2N hydrochloric acidat 0° C., followed by extraction with ethyl acetate. The extract waswashed with aqueous sodium hydrogen carbonate and water and then dried,after which the solvent was distilled off, to yield the title compoundas a colorless crystals (7.18 g).

Melting point: 209°-210° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.09 (1H, bt, J=5.8 Hz), 2.20 (3H, s),2.34 (3H, s), 3.81 (3H, s), 4.43 (2H, d, J=5.8 Hz), 6.73 (1H, s),7.25-7.35 (2H, m), 7.45-7.55 (3H, m), 8.19 (1H, s)

1(2H)-Isoquinolinone-3-carboxylic acids having respective correspondingsubstituents were reduced in the same manner as in Reference Example 47to yield the compounds of Reference Examples 48 to 51 as colorlesscrystals.

Reference Example 48 1,2-Dihydro-3-hydroxymethyl-2-methyl-1-oxo-4-phenylisoquinoline

Melting point: 158°-159° C. (recrystallized from ethyl acetate-isopropylether)

Reference Example 491,2-Dihydro-3-hydroxymethyl-2-methyl-4-(2-methylphenyl)-1-oxoisoquinoline

Melting point: 167°-168° C. (recrystallized from ethyl acetate-isopropylether)

Reference Example 506-Chloro-1,2-dihydro-3-hydroxymethyl-2-methyl-1-oxo-4-phenyisoquinoline

Melting point: 193°-195° C. (recrystallized from ethyl acetate-ethylether)

Reference Example 512-Ethoxycarbonylmethyl-1,2-dihydro-3-hydroxymethyl-6,7-dimethyl-1-oxo-4-phenylisoquinoline

Melting point: 176°-178° C. (recrystallized from ethyl acetate)

Reference Example 521,2-Dihydro-3-methanesulfonyloxymethyl-2,6,7-trimethyl-1-oxo-4-phenylisoquinoline

To a solution of the compound (3.0 g) obtained in Reference Example 47in dichloromethane (100 ml) were added triethylamine. (3.8 ml) andmethanesulfonyl chloride (1.3 ml), while stirring the solution at 0° C.,followed by stirring for 30 minutes. After dichloromethane was added,the reaction mixture was washed with a 5% aqueous phosphoric acidsolution and water and then dried, after which the solvent was distilledoff, to yield the title compound as colorless crystals (2.98 g).

Melting point: 150°-151° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 2.25 (3H, s), 2.40 (3H, s), 2.86 (3H,s), 3.77 (3H, s), 5.01 (2H, s), 6.82 (1H, s), 7.25-7.35 (2H, m),7.45-7.60 (3H, m), 8.27 (1H, s)

Elemental analysis (for C₂₀ H₂₁ NO₄ S):

Calculated: C, 64.67; H, 5.70; N, 3.77

Found: C, 64.59; H, 5.69; N, 3.67

3-Hydroxylmethylisoquinol:ines having respective correspondingsubstituents were reacted with methanesulfonyl chloride in the somemanner as in Reference Example 52 to yield the compounds of ReferenceExample 53 to 55 as colofiess crystals.

Reference Example 531,2-Dihydro-3-methanesulfonyloxymethyl-2-methyl-1-oxo-4-phenylisoquinoline

Melting point: 149°-150° C. (recrystallized from ethyl acetate-isopropylether)

Reference Example 541,2-Dihydro-3-methanesulfonyloxymethyl-2-methyl-4-(2-methylphenyl)-1-oxoisoquinoline

Melting point: 149°-150° C. (recrystallized from ethyl acetate-isopropylether)

Reference Example 55

6-Chloro-1,2-dihydro-3-methanesulfonyloxymethyl-2-methyl-1-oxo-4-phenylisoquinoline

Melting point: 168°-165° C. (recrystallized from ethyl acetate-isopropylether)

Reference Example 56 1,2-Dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolineacetic acid

Process 1:

The compound (6.4 g) obtained in Reference Example 52 was dissolved inDMSO (80 ml), and sodium cyanide (5.0 g) was added, followed by stirringat room temperature for 30 minutes. After ethyl acetate was added, thisreaction mixture was washed with water and then dried, after which thesolvent was distilled off, to yield3-cyanomethyl-1,2-dihydro-2,6,7-trimethyl-1-oxo-4- phenylisoquinoline ascolorless crystals (4.7 g).

Melting point: 186°-188° C. (recrystallized from ethyl acetate-isopropylether)

Process 2:

A mixture of the compound (4.7 g) obtained in Process 1, acetic acid(150 ml) and hydrochloric acid (150 ml) was heated at 110° C. for 7hours. After the solvent was distilled off, ethyl acetate was added tothe residue. The mixture was washed with water and then dried, afterwhich the solvent was distilled off, to yield the title compoundscolorless crystals (3.7 g).

The physico-chemical data of this compound were identical with those ofthe compound obtained in Reference Example 19.

Reference Example 57

The compound obtained in Reference Example 55 was reacted by a methodsimilar to Process 1 and 2 of Reference Example 56 to yield thefollowing compounds.

Process 1:

6-Chloro-3-cyanomethyl-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinoline

Melting point: 229°-231° C. (recrystallized from ethyl acetate)

Process 2:

6-Chloro-1,2-dihydro-2-methyl-1-oxo-4-phenyl-3-isoquinolineacetic acid

Melting point: 216°-217° C. (recrystallized from ethyl acetate-acetone)

Reference Example 581,2-Dihydro-3-(2-hydroxyethyl)-2,6,7-trimethyl-1-oxo-4-phenylisoquinoline

To a solution of the compound (700 mg) obtained in Reference Example 56in THF (10 ml) were added oxalyl chloride (0.3 ml) and DMF (one drop) atroom temperature, followed by stirring for 30 minutes. After the solventwas distilled off, the residue was dissolved in THF (5 ml). Thissolution was gradually added at 0° C. to a suspension of sodiumborohydride (0.5 g) in dimethoxyethane (10 ml). After stirring at 0° C.for 20 minutes, the reaction mixture was added to 2N hydrochloric acidat 0° C., followed by extraction with ethyl acetate. The extract waswashed with aqueous sodium hydrogen carbonate and water and then dried,after which the solvent was distilled off, to yield the title compoundas colorless crystals (571 mg).

Melting point: 204°-207° C. (recrystallized from ethyl acetate-isopropylether) NMR (200 MHz, CDCl₃) ppm: 1.90 (1H, bs), 2.19 (3H, s), 2.34 (3H,s), 2.84 (2H, t, J=7.1 Hz), 3.60-3.80 (2H, m), 3.73 (3H, s), 6.62 (1H,s) 7.20-7.30 (2H, m), 7.35-7.50 (3H, m), 8.16 (1H, s)

Reference Example 592-Ethoxycarbonylmethyl-6,7-dimethyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylicacid

Process 1:

To a solution of the compound (1.172 g) of Reference Example 33 inacetone (20 ml)-DMF (5 ml) were added benzyl bromide (0.586 ml) andpotassium carbonate (608 mg), followed by heating under reflux for 2.5hours. After the solvent was distilled off, ethyl acetate was added tothe residue, which was then washed with water and then dried, followedby solvent removal by distillation, to yield6,7-dimethyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylic acid benzylester as colorless crystals (700 mg).

Melting point: 166°-169° C. (recrystallized from ethyl acetate)

Process 2:

To a solution of the compound (700 mg) obtained in Process 1 in DMF (5ml) was added sodium hydride (60% in oil) (80 mg), followed by stirringat room temperature for 15 minutes. To this mixture was added ethylbromoacetate (0.222 ml) with ice cooling, followed by stirring at roomtemperature for 30 minutes. The reaction mixture was poured into waterand extracted with ethyl acetate, after which the extract was washedwith water and then dried. After the solvent was distilled off, theresidue was subjected to silica gel column chromatography (hexane:ethylacetate=9:1) to yield2-ethoxycarbonylmethyl-6,7-dimethyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylicacid benzyl ester as colorless crystals (450 mg).

Melting point: 139.5°-140.5° C. (recrystallized from ethylacetate-hexane)

Process 3:

To a solution of the compound (400 mg) obtained in Process 2 in ethanol(15 ml) was added 10% palladium carbon (100 mg), followed by stirring atroom temperature in a hydrogen atmosphere for 1.5 hours. The catalystwas filtered off, and the filtrate was distilled to remove the solvent.The residue was subjected to silica gel column chromatography(chloroform:methanol=4:1) to yield the title compound as colorlesscrystals (280 mg).

Melting point: 210°-213° C. (recrystallized from methanol)

Reference Example 602-(3-Ethoxycarbonylpropyl)-4-phenyl-1(2H)-isoquinolinone-3-carboxylicacid

A mixture of 4-phenylisocoumarin-3-carboxylic acid (1.30 g),4-amino-n-butyric acid ethyl ester (2.75 g) and ethanol (8 ml) washeated under reflux for 14 hours while stirring. After the solvent wasdistilled off, ethyl acetate was added to the residue. This mixture waswashed with dilute hydrochloric acid and water and then dried, afterwhich the solvent was distilled off. To the residue were added ethylacetate (10 ml) and 4N HCl-ethyl acetate (20 ml), followed by stirringat room temperature for 3 hours. After ethyl acetate was added, thereaction mixture was washed with water and then dried, followed bysolvent removal by distillation, to yield the title compound ascolorless crystals (1.83 g).

Melting point: 154°-156° C. (recrystallized from ethyl acetate-ethylether)

Reference Example 61 1-Amino-1,2,3,4-tetrahydro-6-oxo-11-phenyl-6H-benzo b!quinolizine

Process 1:

The compound (393 mg) obtained in Reference Example 60 was dissolved inDMF (2 ml). While stirring this solution with ice cooling, sodiumhydride (60% in oil) (50 mg) was added, followed by stirring for 15minutes. To this mixture was added ethyl iodide (0.15 ml), followed bystirring at room temperature for 2 hours, after which the solvent wasdistilled off. To the residue was added ethyl acetate, and the mixturewas washed with water and then dried, after which the solvent wasdistilled off, to yield2-(3-ethoxycarbonylpropyl)-4-phenyl-1(2H)-isoquinolinone-3-carboxylicacid ethyl ester as colorless crystals (390 mg).

Melting point: 98°-99° C. (recrystallized from ethyl acetate-isopropylether)

Process 2:

The compound (6.75 g) obtained in Process 1 was dissolved in dry THF(150 ml). While stirring this solution at room temperature, sodiumhydride (60% in oil) (1.50 g) was added. This mixture was heated underreflux for 1 hour. After the reaction mixture was concentrated, ethylacetate was added to the concentrate, which was then washed successivelywith dilute hydrochloric acid, water and aqueous sodium hydrogencarbonate and then dried, after which the solvent was distilled off, toyield 2-ethoxycarbonyl-1,2,3,4-tetrahydro-1,6-dioxo-11-phenyl-6H-benzob!quinolizine as pale yellow crystals (5.25 g).

Melting point: 167°-169° C. (recrystallized from ethyl acetate) NMR (200MHz, CDCl₃) ppm: 1.33 (3H, t, J=7 Hz), 2.67 (2H, t, J=6 Hz), 4.27 (4H,m), 7.06-7.55 (8H, m), 8.51 (1H, m), 12.04 (1H, s) This product has anenol structure.!

Process 3:

A mixture of the compound (2.0 g) obtained in Process 2, acetic acid (15ml), concentrate hydrochloric acid (4 ml), ethanol (3 ml) and water (3ml) was heated under reflux for 5 hours while stirring, followed bysolvent removal by distillation. To the residue was added water, and theprecipitated crystals were collected by filtration and then washed withwater, ethanol and ether, to yield1,2,3,4-tetrahydro-1,6-dioxo-11-phenyl-6H-benzo b!quinolizine as yellowcrystals (1.48 g).

Melting point: 223°-225° C. (recrystallized from ethyl acetate) NMR (200MHz, CDCl₃) ppm: 2.27 (2H, m), 2.67 (2H, t, J=6.5 Hz), 4.37 (2H, m),7.15-7.62 (8H, m), 8.55 (1H, m)

Elemental analysis (for C₁₉ H₁₅ NO₂):

Calculated: C, 78.87; H, 5.23; N, 4.84

Found: C, 78.65; H, 5.36; N, 4.88

Process 4:

A mixture of the compound (1.16 g) obtained in Process 3, hydroxylaminehydrochloride (2.78 g), sodium acetate (3.28 g) and ethanol (50 ml) washeated under reflux for 4 hours, followed by solvent removal bydistillation. To the residue was added water, and the precipitatedcolorless crystals were collected by filtration and then washed withwater, ethanol and ether, to yield an oxime derivative as colorlesscrystals (1.18 g) .

Melting point: 277°-279° C. (decomposed) (recrystallized fromchloroform-methanol) NMR (200 MHz, CDCl₃) ppm: 2.04 (2H, m), 2.80 (2H,t, J=7.4 Hz), 2.23 (2H, m), 7.20-7.55 (8H, m), 8.52 (1H, m)

Process 5:

To a suspension of the compound (500 mg) obtained in Process 4 inethanol (20 ml) were added ammonium acetate (138 mg), zinc powder (520mg) and 40% aqueous ammonia (10 ml), followed by heating under refluxfor 5 hours. The precipitate was filtered off, and the filtrate wasdistilled to remove the solvent. After ethyl acetate was added, theresidue was washed with water. The ethyl acetate layer was extractedwith 2N HCl. The extract was alkalinized by addition of potassiumcarbonate and then extracted with ethyl acetate, washed with water andthen dried, after which the solvent was distilled off, to yield thetitle compound as colorless crystals (205 mg).

Melting point: 183°-185° C. (recrystallized from ethyl acetate-ether)NMR (200 MHz, CDCl₃) ppm: 1.7-2.3 (4H, m), 4.13 (1H, t, J=3 Hz), 4.32(2H, t, J=7 Hz), 6.96 (1H, m), 7.26-7.55 (7H, m), 8.49 (1H, m)

Reference Example 621,2,3,4-Tetrahydro-1-hydroxy-6-oxo-11-phenyl-6H-benzo b!quinolizine

To a suspension of the compound (250 mg) obtained in process 3 ofReference Example 61 in methanol (15 ml) was added sodium borohydride(40 mg) at room temperature, followed by stirring for 1 hour. Thereaction mixture was concentrated, and dilute hydrochloric acid wasadded to the concentrate, followed by extraction with ethyl acetate. Theextract was washed with water and then dried, after which the solventwas distilled off, to yield the title compound as pale yellow crystals(235 mg).

Melting point: 220°-222° C. (recrystallized from ethyl acetate) NMR (200MHz, CDCl₃) ppm: 1.70-2.30 (4H, m), 4.10-4.45 (2H, m), 4.75 (1H, t,J=3.2 Hz), 6.99-7.03 (1H, m), 7.25-7.53 (7H, m), 8.49 (1H, m)

Reference Example 632-(3-Ethoxycarbonylpropyl)-6,7-dimethyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylicacid

The compound obtained in Process 1 of Reference Example 29 and4-amino-n-butyric acid ethyl ester were reacted and treated in the samemanner as in Reference Example 60 to yield the title compound as acolorless oily substance.

NMR (200 MHz, CDCl₃) ppm: 1.13 (3H, t, J=7.2 Hz), 2.16 (2H, m), 2.26(3H, s), 2.39 (3H, s), 2.42 (2H, m), 3.97 (2H, q, J=7.2 Hz), 4.16 (2H,m), 6.92 (1H, s), 7.32-7.48 (3H, m), 8.23 (1H, s)

Reference Example 64 1-Amino-1,2,3,4-tetrahydro-6-oxo-11-phenyl-6H-benzob!quinolizine

The compound obtained in Reference Example 63 was reacted and treated inthe same manner as in Process 1 through 5 of Reference Example 61 toyield the title compound. The intermediate compounds obtained in therespective process and their physico-chemical constants are given below.

Process 1:

2-(3-Ethoxycarbonylpropyl)-6,7-dimethyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylicacid ethyl ester

A colorless oily substance

NMR (200 MHz, CDCl₃) ppm: 0.90 (3H, t, J=7.2 Hz), 1.25 (3H, t, J=7.2Hz), 2.12 (2H, m), 2.26 (3H, s), 2.39 (2H, m), 2.40 (3H, s), 3.95-4.20(6H, m), 6.95 (1H, s), 7.24-7.50 (5H, m), 8.25 (1H, s)

Process 2:

2-Ethoxycarbonyl-1,2,3,4-tetrahydro-8,9-dimethyl-1,6-dioxo-11-phenyl-6H-benzob!quinolizine

Melting point: 166°-168° C. (recrystallized from ethyl acetate)

Process 3:

1,2,3,4-Tetrahydro-8,9-dimethyl-1,6-dioxo-11-phenyl-6H-benzob!quinolizine

Melting point: 203°-206° C. (recrystallized from ethyl acetate)

Process 4:

1,2,3,4-Tetrahydro-1-hydroxyimino-8,9-dimethyl-1,6-dioxo-11-phenyl-6H-benzob!quinolizine

Melting point: 247°-250° C. (decomposed) (recrystallized from ethanol)

Process 5:

Title compound (recrystallized from ethyl acetate)

Melting point: 175°-177° C. (recrystallized from ethyl acetate)

Reference Example 651,2,3,4-Tetrahydro-1-hydroxy-8,9-dimethyl-6-oxo-11-phenyl-6H-benzob!quinolizine

The compound obtained in Process 3 of Reference Example 64 was reacted(reduced) and treated in the same manner as in Reference Example 62 toyield the title compound as colorless crystals.

Melting point: 210°-212° C. (recrystallized from ethyl acetate)

Reference Example 66 1,2,3,4-Tetrahydro-1,6-dioxo-11-phenyl-6H-pyrazino1,2-b!isoquinoline

A mixture of 1-oxo-4-phenyl-1H-2-benzopyran-3-carboxylic acid (500 mg)and ethylenediamine (15 ml) was stirred at room temperature overnight.After evaporation of the solvent, concentrated hydrochloric acid (10 ml)and acetic acid (10 ml) were added to the residue. The mixture washeated under reflux for 48 hours. To the mixture was added water, andextracted with ethyl acetate. The extract was washed successively withwater, aqueous sodium hydrogen carbonate and water, dried, andevaporated to yield the title compound as colorless crystals (115 mg).

Melting point: >300° C. (recrystallized from ethyl acetate)

Reference Example 67 1,2,3,4-Tetrahydro-6-oxo-11 -phenyl-6H-pyrazino1,2-b!isoquinoline

Process 1:

1-Oxo-4-phenyl-1H-2-benzopyran-3-carboxylic acid (3.0 g) was subjectedto reduction by a method similar to Reference Example 47 to yield3-hydroxymethyl-1-oxo-4-phenyl-1H-2-benzopyran as colorless crystals(2.6 g).

Melting point: 109°-110° C. (recrystallized from ethyl acetate-hexane)

Process 2:

The compound obtained in Process 1 (2.5 g) was oxidized with SO₃-pyridine complex in DMSO in the presence of triethylarnine to yield1-oxo-4-phenyl-1H-2-benzopyran-3-carboxaldehyde as colorless crystals(2.38 g).

Melting point: 179°-181° C. (recrystallized from ethyl acetate-THF)

Process 3:

A mixture of the compound obtained in Process 2 (500 mg) andethylenedismine (15 ml) was stirred at room temperature for 5 hours.After evaporation of the solvent, water was added to the residue, andthe mixture was extracted with ethyl acetate. The extract was washedwith water, dried, and evaporated. To the residue was added concentratedhydrochloric acid (5 ml) and the mixture was stirred at room temperatureovernight. After neutaralization, the mixture was extracted with ethylacetate. The extract was washed with water, dried, and evaporated toyield 3,4-dihydro-6-oxo-11-phenyl-6H-pyrazino 1,2-b!isoquinoline ascolor crystals (280 mg).

Melting point: 181°-183° C. (recrystallized from ethyl acetate)

Process 4:

To a mixture of the compound obtained in Process 3 (260 mg), acetic acid(60 μl) and methnol (10 ml) was added sodium cyanoborohydride (120 mg),and the mixture was stirred for 30 minutes at room temperature. Afterevaporation of the solvent, aqueous sodium hydrogen carbonate was addedto the residue, and the mixture was extracted with ethyl acetate. Theextract was washed with water, dried, and evaporated to yield the titlecompound as colorless crystals (240 mg).

Melting point: 154°-156° C. (recrystallized from ethyl acetate)

Reference Example 681,2-Dihydro-3-mercaptomethyl-2-methyl-4-(2-methylphenyl)-1-oxoisoquinoline

A mixture of the compound obtained in Reference Example 54 (1.8 g),sodium hydrosulfide-methanol solution (2.73M) (3 ml), THF (25 ml), andmethanol (10 ml) was stirred for 1 hour at room temperature. Afterevaporation of the solvent, dilute hydrochloric acid was added to theresidue, and the mixture was extracted with ethyl acetate. The extractwas washed with dilute hydrochloric acid and water, dried, andevaporated. The residue was subjected to silica gel columnchromatography (ethyl acetate:hexane=3:1) to yield the title compound ascolorless crystals (503 mg).

Melting point: 184°-186° C. (recrystallized from ethyl acetate-isopropylether)

FORMULATION EXAMPLE Tablets

Of the components given below, to the compound of Example 101, cornstarch and lactose were added with aqueous hydroxypropylcellulose, andthe mixture was kneaded, then dried and crushed to give granules.

To this was added magnesium stearate and, after admixing, the wholemixture was made up into tablets each weighing 200 mg on a rotarytableting machine.

Composition per tablet:

    ______________________________________                                        Compound of Example 101 50 mg                                                 Lactose                 100 mg                                                Corn starch             43.4 mg                                               Hydroxypropylcellulose  6 mg                                                  Magnesium stearate      0.6 mg                                                Total                   200 mg                                                ______________________________________                                    

We claim:
 1. A compound represented by the general formula: ##STR107##wherein ring A" and ring B independently represent an optionallysubstituted benzene ring;either X or Y represents --NR¹ -- (R¹represents a hydrogen atom, an optionally substituted hydrocarbon group,an optionally substituted hydroxyl group or an optionally substitutedamino group), the other representing --CO--, --CS-- or --C(R²)R^(2a) --(R² and R^(2a) independently represent a hydrogen atom or an optionallysubstituted hydrocarbon group), or either X or Y represents --N═, theother representing ═CR³ -- (R³ represents a hydrogen atom, a halogenatom, an optionally substituted hydrocarbon group, an optionallysubstituted amino group, a substituted hydroxyl group or a mercaptogroup substituted by an optionally substituted hydrocarbon group);........ represent a single or double bond; (i) when ........ adjacentto Z is a single bond, Z represents ##STR108## (R⁴ represents a hydrogenatom, hydroxyl group or an optionally substituted hydrocarbon group), or(ii) when ........ adjacent to Z is a double bond, Z represents a carbonatom; D represents a C₁₋₃ alkylene group which may be substituted by anoxo group or a thioxo group, or D and Y, taken together, may form a 5-to 7- membered ring which may be substituted by an oxo group or a thioxogroup; E represents --NR⁵ -- (R⁵ represents a hydrogen atom or anoptionally substituted hydrocarbon group), --O-- or --S(O)n-- (n is 0,1or 2), or R⁵ and Y, taken together, may form a 5- to 7- membered ringwhich may be substituted by an oxo group or a thioxo group; G representsa bond or a C₁₋₃ alkylene group; Ar represents an optionally substitutedaryl group, provided that (1) when --X--Y-- represents --NH--CO--, Drepresents --CO--.
 2. A compound as claimed in claim 1, wherein either Xor Y represents --NR¹ --, the other representing --CO--, --CS-- or--C(R²)R^(2a) -- wherein R¹, R² and R^(2a) represent the same meaningsas defined in claim
 1. 3. A compound as claimed in claim 1, wherein--X--Y-- represents --CO--NR¹ -- or --NR¹ --CO-- wherein R¹ representsthe same meaning as defined in claim
 1. 4. A compound as claimed inclaim 1, wherein --X--Y-- represents --NR¹ -- C(R²)R^(2a) -- or--C(R²)R^(2a) --NR¹ -- wherein R¹, R² and R^(2a) represent the samemeanings as defined in claim
 1. 5. A compound as claimed in claim 1,wherein --X--Y-- represents --N═CR³ -- wherein R³ represents the samemeaning as defined in claim
 1. 6. A compound as claimed in claim 1,wherein --X--Y-- represents --CS--NR¹ -- wherein R¹ represents the samemeaning as defined in claim
 1. 7. A composition for inhibiting acyl-CoA:cholesterol acyl transferase which comprises an effective amount of acompound of the formula: ##STR109## wherein ring A" and ring Bindependently represent an optionally substituted benzene ring; either Xor Y represents --NR¹ -- (R¹ represents a hydrogen atom, an optionallysubstitutedhydrocarbon group, an optionally substituted hydroxyl groupor an optionally substituted amino group), the other representing--CO--, --CS-- or --C(R²)R^(2a) -- (R² and R^(2a) respectively representa hydrogen atom or an optionally substituted hydrocarbon group), oreither X or Y represents --N═, the other representing ═CR³ -- (R³represents a hydrogen atom, a halogen atom, an optionally substitutedhydrocarbon group, an optionally substituted amino group, an optionallysubstituted alkoxy group or a mercapto group substituted by anoptionally substituted hydrocarbon group);........ represent a single ordouble bond; (i) when ........ adjacent to Z is a single bond, Zrepresents ##STR110## (R⁴ represents a hydrogen atom or an optionallysubstituted hydrocarbon group), or (ii) when ........ adjacent to Z is adouble bond, Z represents a carbon atom; D represents a C₁₋₃ alkylenegroup which may be substituted by an oxo group or a thioxo group, or Dand Y, taken together, may form a 5- to 7- membered ring which may besubstituted by an oxo group or a thioxo group; E represents --NR⁵ -- (R⁵represents a hydrogen atom or an optionally substituted hydrocarbongroup), --O-- or --S(O)n-- (n is 0,1 or 2), or R⁵ and Y, taken together,may form a 5- to 7- membered ring which may be substituted by an oxogroup or a thioxo group; G represents a bond or a C₁₋₃ alkylene group;Ar represents an optionally substituted aryl group or a pharmaceuticallyacceptable salt and a physiologically acceptable carrier.
 8. Acomposition for lowering cholesterol in blood which comprises aneffective amount of a compound as claimed in claim 7, or apharmaceutically acceptable salt and a physiologically acceptablecarrier.
 9. A tachykinin receptor antagonist composition which comprisesan effective amount of a compound as claimed in claim 7, or apharmaceutically acceptable salt and a physiologically acceptablecarrier.
 10. A substance P receptor antagonist composition whichcomprises an effective amount of a compound as claimed in claim 7, or apharmaceutically acceptable salt and a physiologically acceptablecarrier.
 11. A process for producing a compound of claim 1 whichcomprises reacting a compound of the formula: ##STR111## wherein Lrepresents a leaving group; D and Y do not bind together to form a 5- to7- membered ring; the other symbols are the same meaning as defined inclaim 1 or salt thereof with a compound of the formula:

    H--E--G--Ar

wherein all symbols are the same meaning as defined in claim 1 or a saltthereof.
 12. A process for producing a compound of claim 1 whichcomprises reacting a compound of the formula: ##STR112## wherein allsymboles are the same meaning as defined in claim 1 or salt thereof witha compound of the formula:

    L'G--Ar

wherein L' represents a leaving group; the other symbols are the samemeaning as defined in claim 1 or a salt thereof.
 13. Method for treatinghypercholesterolemia in mammals which comprises administrating to asubject in need therefrom an effective amount of a compound as claimedin claim 7 or a pharmaceutically acceptable salt and a physiologicallyacceptable carrier.
 14. Method for treating pain in mammals whichcomprises administrating to a subject in need therefrom an effectiveamount of a compound as claimed in claim 7 or a pharmaceuticallyacceptable salt and a physiologically acceptable carrier.
 15. Method fortreating disturbances of micturition in mammals which comprisesadministrating to a subject in need therefrom an effective amount of acompound as claimed in claim 7 or a pharmaceutically acceptable salt anda physiologically acceptable carrier.
 16. Method for antagonizing atachykinin recepter in mammals which comprises administrating to asubject in need an effective amount of a composition as claimed in claim7 or a pharmaceutically acceptable salt and a physiologically acceptablecarrier.
 17. A compound as claimed in claim 1, wherein ring A"represents a benzene ring which may be substituted by two C₁₋₄ alkylgroups; ring B represents a benzene ring which may be substituted by aC₁₋₄ alkyl group or a halogen atom;--X--Y-- represents --CO--NH--CH₂--or --CO--N(CH₃)--; Z represents a carbon atom; ........ represents adouble bond; --D--E--G-- represents --CONH--CH₂ -- or --CON(CH₃)--CH₂--; and Ar represents a phenyl group substituted by one or twooptionally halogenated C₁₋₄ alkyl group(s).
 18. A compound as claimed inclaim 1, wherein ring A" and B represent an unsubstituted benzenering;--X--Y-- represents --N═CH--, --N═CCl--, --N═C(NHCH₃)--; Zrepresents a carbon atom; ........ represents a double bond; --D--E--G--represents --CON(CH₃)--CH₂ --; and Ar represents a phenyl groupsubstituted by two optionally halogenated C₁₋₄ alkyl groups.
 19. Acompound as claimed in claim 1, wherein ring A" represents a benzenering which may be substituted by a halogen atom or a C₁₋₄ alkylgroup;ring B represents a benzene. ring which may be substituted by ahalogen atom; --X--Y-- represents --N(CH₃)--CO--, --N(CH₃)--CH₂ --,--N═CH-- or --N═C(OCH₃)--; Z represents ##STR113## ........ represents asingle bond or a double bond; --D--E--G-- represents --CH₂ --CONH--; andAr represents a phenyl group substituted by one to three optionallyhalogenated C₁₋₄ alkyl group(s), C₁₋₄ alkoxy group(s) or halogenatom(s).
 20. A compound as claimed in claim 1 which is the generalformula: ##STR114## wherein rings A', B' and J independently representan optionally substituted benzene ring;either X' or Y' represents--NR^(1a) -- (R^(1a) represents an optionally substituted hydrocarbongroup), the other representing --CO--, --CS-- or --C(R²)R^(2a) -- (R²and R^(2a) independently represent a hydrogen atom or an optionallysubstituted hydrocarbon group), or either X' or Y' represents --N═, theother representing ═CR^(3a) --(R^(3a) represents a hydrogen atom, anoptionally substituted hydrocarbon group or --OR wherein R represents anoptionally substituted hydrocarbon group; ........ represents a singleor double bond; (i) when ........ is a single bond, Z' represents##STR115## (R^(4a) represents a hydrogen atom or an optionallysubstituted hydrocarbon group), or when ........ is a double bond, Z'represents a carbon atom; α represents 0, 1 or 2, or a salt thereof. 21.A compound as claimed in claim 20, wherein --X'--Y'-- is the formula:--NR^(1a) --CO--, --NR^(1a) --C(R²)R^(2a) --, or --N═CR^(3a) --, whereinthe symbols have the same definitions as in claim
 20. 22. A process forproducing a compound represented by the general formula: ##STR116##wherein the symbols have the same definitions as in claim 20, or a saltthereof, characterized by reaction of a compound represented by thegeneral formula: ##STR117## wherein the symbols have the samedefinitions as in claim 20, or a salt or reactive derivative thereof,and a compound represented by the general formula: ##STR118## whereinthe symbols have the same definitions as in claim 20, or a salt thereof.23. A composition for inhibiting acyl--CoA: cholesterol acyl transferacewhich comprises an effective amount of a compound of the formula:##STR119## wherein rings A', B' and J independently represent anoptionally substituted benzene ring; either X" or Y" represents--NR^(1b) -- (R^(1b) represents a hydrogen atom or an optionallysubstituted hydrocarbon group), the other representing --CO--, --CS-- or--C(R²)R^(2a) -- (R² and R^(2a) independently represent a hydrogen atomor an optionally substituted hydrocarbon group), or either X" or Y"represents --N═, the other representing ═CR^(3a) -- (R^(3a) represents ahydrogen atom, an optionally substituted hydrocarbon group or --ORwherein R represents an optionally substituted hydrocarbongroup);........ represents a single or double bond; (i) when ........adjacent to Z' is a single bond, Z' represents ##STR120## (R^(4a)represents a hydrogen atom or an optionally substituted hydrocarbongroup) or (ii) when ........ adjacent to Z' is a double bond,Z'represents a carbon atom; α represents 0, 1 or 2, or apharmaceutically acceptable salt and a physiologically acceptablecarrier.
 24. A compound as claimed in claim 1 which is the generalformula: ##STR121## wherein rings A" and B" are an optionallysubstituted benzene ring; R^(1c) represents a hydrogen atom, a hydroxylgroup, an optionally substituted hydrocarbon group, an optionallysubstituted alkoxy group or an optionally substituted amino group;Qrepresents an oxygen atom or a sulfur atom; D¹ represents a C₁₋₃alkylene group which may be substituted by an oxo group or a thioxogroup; provided that when D¹ is an unsubstituted C₁₋₃ alkylene group, itmay cooperate with R^(1c) to form a 5- to 7-membered ring which may besubstituted by an oxo or thioxo group; E² represents --NR^(5a) --(R^(5a) represents a hydrogen atom or an optionally substitutedhydrocarbon group), --O-- or --S--; R^(5a) and R^(1c), take together,may form a 5- to 7-membered ring which may be substituted by an oxo orthioxo group; G³ represents a bond or a C₁₋₃ alkylene group; Ar'represents an optionally substituted aryl group provided that when --D¹--E² -- represents --(CH₂).sub.β --CONH--(.sub.β is 0, 1 or 2), G³represents a C₁₋₃ alkylene group, or a salt thereof.
 25. A compound asclaimed in claim 24, wherein rings A" and B" are a benzene ring whichmay be substituted by one to four substituents selected from the groupconsisting of a halogen, an optionally halogenated C₁₋₄ alkyl group, ahydroxyl group, an optionally halogenated C₁₋₄ alkoxy group, anoptionally halogenated C₁₋₄ alkylthio group, an amino group, a mono- ordi- C₁₋₄ alkylamino group, a carboxyl group and a C₁₋₄ alkoxy-carbonylgroup.
 26. A compound as claimed in claim 24, wherein ring A" isrepresented by the general formula: ##STR122## wherein A^(4a), A^(5a)and A^(6a), independently represent a halogen atom, an optionallyhalogenated C₁₋₄ alkyl group or an optionally halogenated C₁₋₄ alkoxygroup.
 27. A compound as claimed in claim 24, wherein ring B" isrepresented by the general formula: ##STR123## wherein B^(4b), B^(5b)and B^(6b), independently represent a halogen atom, an optionallyhalogenated C₁₋₄ alkyl group or an optionally halogenated C₁₋₄ alkoxygroup.
 28. The compound as claimed in claim 24, wherein R^(1c) is ahydrogen atom or a C₁₋₄ alkyl group which may be substituted by one ortwo substituents selected from the group consisting of hydroxyl group,C₁₋₄ alkoxy group, amino group, mono- or di-C₁₋₄ alkylamino group, C₁₋₄alkoxy-carbonyl group, carboxyl group, carbamoyl group and phenyl group.29. A compound as claimed in claim 24, wherein R^(1c) is a hydrogen atomor a C₁₋₄ alkyl group.
 30. A compound as claimed in claim 24, whereinR^(5a) is a hydrogen atom or a C₁₋₄ alkyl group which may be substitutedby one or two substituents selected from the group consisting of ahydroxyl group, a C₁₋₄ alkoxy group, an amino group, a mono- or di-C₁₋₄alkylamino group, a C₁₋₄ alkoxy-carbonyl group, carboxyl group,carbamoyl group and phenyl group.
 31. A compound as claimed in claim 24,wherein R^(5a) is a hydrogen atom or a C₁₋₄ alkyl group.
 32. A compoundas claimed in claim 24, wherein the optionally substituted aryl grouprepresented by Ar, is a C₆₋₁₀ aryl group which may be substituted by oneto three substituents selected from the group consisting of anoptionally halogenated C₁₋₄ alkyl group, a halogen atom, a nitro group,a hydroxyl group, an optionally halogenated C₁₋₄ alkoxy group, an aminogroup, a mono- or di-C₁₋₄ alkylamino group, a C₁₋₄ alkoxy-carbonylgroup, a Carboxyl group and a carbamoyl group.
 33. A compound as claimedin claim 24, wherein Ar is a phenyl group which may have one to threesubstituents selected from the group consisting of an optionallyhalogenated C₁₋₄ alkyl group, halogen atom and C₁₋₄ alkoxy group.
 34. Acompound as claimed in claim 24, wherein Q is an oxygen atom.
 35. Acompound as claimed in claim 24, wherein D¹ is --CO--, --CS--, --CH₂ --,--CH₂ CH₂ --, --CH₂ CO-- or --CH₂ CH₂ CO--.
 36. A compound as claimed inclaim 24 wherein D¹ is --CO-- or --CH₂ CO--.
 37. A compound as claimedin claim 24, wherein D¹ is --CH₂ -- or --CH₂ CH₂ --.
 38. A compound asclaimed in claim 24, wherein D¹ is --CO-- or --CH₂ --.
 39. A compound asclaimed in claim 24, wherein E² is --NR^(5c) -- wherein R^(5c) is ahydrogen atom or a C₁₋₄ alkyl group.
 40. A compound as claimed in claim24, wherein E² is --O--.
 41. A compound as claimed in claim 24, whereinG³ is --CH₂ -- or --CH₂ CH₂ --.
 42. A compound as claimed in claim 24;wherein ring A" is a benzene ring which may be substituted by two C₁₋₄alkyl groups;ring B" is a benzene ring which may be substituted by aC₁₋₄ alkyl group; R^(1c) is a C₁₋₄ alkyl group; D¹ is --CO--; E² is--NR^(5c) -- wherein R^(5c) represents a hydrogen atom or a C₁₋₄ alkylgroup; G³ is --CH² --; and Ar is a phenyl group substituted by one tothree halogenated C₁₋₄ alkyl groups.
 43. A compound as claimed in claim24 which isN-(3,5-bistrifluoromethyl)benzyl-1,2-dihydro-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxsmide,N-(3,5-bistrifluoromethyl)benzyl-1,2-dihydro-N,2-dimethyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamideorbis(trifluoromethyl)benzyl!-1,2-dihydro-N,2,6,7-tetramethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide.44. A tachykinin receptor antagonist composition containing a compoundrepresented by the general formula: ##STR124## wherein rings A" and B"are an optionally substituted benzene ring; R^(1c) represents a hydrogenatom, a hydroxyl group, an optionally substituted hydrocarbon group, anoptionally substituted alkoxy group or an optionally substituted aminogroup;Q represents an oxygen atom or a sulfur atom; D¹ represents a C₁₋₃alkylene group which may be substituted by an oxo or thioxo group;provided that when D¹ is an unsubstituted C₁₋₃ alkylene group, it maycooperate with R^(1c) to form a 5- to 7-membered ring which may besubstituted for by an oxo or thioxo group; E² represents --NR^(5a) --(R^(5a) represents a hydrogen atom or an optionally substitutedhydrocarbon group), --O-- or --S--; R^(5a) and R^(1c) may bind togetherto form a 5- to 7-membered ring which may be substituted by an oxo orthioxo group; G³ represents a bond or a C₁₋₃ alkylene group; Ar'represents an optionally substituted aryl group; provided that when D¹is --(CH₂).sub.β --CO-- (.sub.β is 0, 1 or 2) and D² is --NH--, Zrepresents a C₁₋₃ alkylene group, or a pharmaceutically acceptable saltand a pharmaceutically acceptable carrier.
 45. A tachykinin receptorantagonist composition containing the compound of claim
 24. 46. atachykinin antagonist of claim 44 wherein the tachykinin receptor is asubstance P receptor.
 47. A substance P receptor antagonist compositioncontaining the compound of claim
 24. 48. A process for producing acompound of claim 24 which comprises reacting a compound of the formula:##STR125## wherein L represents a leaving group; D¹ and R^(1c) do notbind together to form a 5- to 7- membered ring; the other symboles arethe same meaning as defined in claim 24 or a salt thereof with acompound of the formula:

    H--E--G--Ar

wherein all symboles are the sine meanings as defined in claim 24 or asalt thereof.
 49. A process for producing a compound of claim 24 whichcomprises reacting a compound of the formula: ##STR126## wherein allsymboles are the same meaning as defined in claim 24 or salt thereofwith a compound of the formula:

    L'--G--Ar

wherein L' represents a leaving group; the other symboles are the samemeaning as defined in claim 24 or a salt thereof.
 50. A compound asclaimed in claim 1, which is;N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N-ethyl-2-methyl-1-oxo-4-phenyl-3-isoiquinolinecarboxamide,N-3,5-Bis(trifluoromethyl)benzyl!-5-fluoro-4-(4-fluorophenyl)-N,2-dimethyl-1-oxo-3-isoquinolinecarboxamide,N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-2-ethyl-N-methyl-1-oxo-4-phenyl-3-isoiquinolinecarboxamide,N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoiquinolinecarboxamide,N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N-methyl-2-oxo-4-phenyl-3-quinolinecarboxamide,N-3,5-Bis(trifluoromethyl)benzyl!-4-(2-chlorophenyl)-1,2-dihydro-N,1-dimethyl-2-oxo-3-quinolinecarboxamide,N-3,5-Bis(trifluoromethyl)benzyl!-1-chloro-4-(4-fluorophenyl)-N-methyl-3-isoquinolinecarboxamide,N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N,2-dimethyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarboxamide,N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N,2-dimethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide,N-3,5-Bis(trifluoromethyl)benzyl!-4-(4-fluorophenyl)-1,2-dihydro-N,2-dimethyl-1-oxo-3-isoquinolinecarboxamide,N- 3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N-methyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide, N-3,5-Bis(trifluoromethyl)benzyl!-4-(4-fluoro-2-methylphenyl)-1,2-dihydro-N,2-dimethyl-1-oxo-3-isoquinolinecarboxamide,N-3,5-Bis(trifluoromethyl)benzyl!-4-(4-fluorophenyl)-1,2-dihydro-N-methyl-1-oxo-3-isoquinolinecarboxamide,N-3,5-Bis(trifluoromethyl)benzyl!-1,2,5,6,7,8-hexahydro-N,2-dimethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide,N-3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N,1-dimethyl-2-oxo-4-phenyl-3-quinolinecarboxamide,N-3,5-Bis(trifluoromethyl)benzyl!-N-methyl-4-phenyl-3-quinolinecarboxamideN-3,5-Bis(trifluoromethyl)benzyl!-N,2-dimethyl-4-phenyl-3-quinolinecarboxamide,N-3,5-Bis(trifluoromethyl)benzyl!-2-chloro-N-methyl-4-phenyl-3-quinolinecarboxamide,N-3,5-Bis(trifluoromethyl)benzyl!-N-methyl-2-methylamino-4-phenyl-3-quinolinecarboxamideor N-3,5-Bis(trifluoromethyl)benzyl!-1-chloro-N-methyl-4-phenyl-3-isoquinolinecarboxarnide,or a salt thereof.
 51. A method of preparing a tachykinin receptorantagonizing composition, comprising combining a therapeuticallyeffective amount of the compound of claim 1 or a pharmaceuticallyacceptable salt with a physiologically acceptable carrier.
 52. A methodof preparing an inhibitory composition for the biosynthesis ofcholesterol, comprising combining a therapeutically effective amount ofthe compound of claim 1 or a pharmaceutically acceptable salt with aphysiologically acceptable carrier.